Disclaimer

*Results may vary. The information in this site is NOT to be construed as medical advice. Cirrhosis of the liver is a serious condition and if you have it, you should see a doctor. I am not a doctor and am not able to dispense medical advice. My husband saw a doctor (many of them) and they were able to do things for him that I could not. However, they were unable to recommend alternative treatments, and in MY OPINION they were VERY beneficial to my husband, so I am providing some of that information here. My husband and I tried all of these alternative therapies at our own risk, and if you try them you will be doing the same. At your own risk. No promises are made in this blog. I am not saying there is a cure for cirrhosis or any other condition. However, I believe most people can get well, like my husband did. My husband is alive, happy, productive, functional and has his energy back. He no longer has to take medications and he no longer worries about having to go on disability or getting a $577,000 liver transplant. Cirrhosis is a serious condition. He is currently in the fibrosis stage (Stage 2 liver disease), which is still serious. I cannot guarantee you will have the same results. I just want you to know about what worked well for my husband. I hope you will share what you learned with others, and share your story with us as well. This blog was made for YOU! Thanks for visiting!

Thursday, January 4, 2018

Rifaximin to reduce the risk of Hepatic Encephalopathy

Note, if you are reading this article because you've been prescribed Rifaximin, please also read THIS POST, about how Probiotics are shown to be helpful for reducing the risk of encephalopathy. I can't tell you NOT to take the Rifaximin... I just think you should know about everything that's out there. Encephalopathy is extremely serious, can cause brain damage, coma, or cost you your LIFE, so you should take this very seriously.  Please also read THIS POST about how red meat and dairy products can make your situation way, way worse!  Unfortunately, many doctors will never tell you how dangerous it can be to eat red meat. 

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Today I was looking up the side effects of Rifaximin, and I have to say I was pleasantly surprised to see that there were a lot of positive reports on how much this stuff appears to reduce the bacteria that causes encephalopathy.  Though I think it is still possible that antibiotics can cause liver failure, I haven't found evidence that this one does. It doesn't mean that it DOESN'T (I only spent 20 minutes on this and sometimes it takes an hour of googling to find critical information, so I suggest you do your own research!)


But I have to say, this part (that you'll see further down the page) disturbs me.... why wouldn't they list all the side effects? Did someone tell them to remove that part? Or maybe I'm just being paranoid.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


This is the page on RxList:

 https://www.rxlist.com/xifaxan-drug/patient-images-side-effects.htm

Brand Names: Xifaxan

Generic Name: rifaximin (Pronunciation: rif AX i min)


What is rifaximin (Xifaxan)?

Rifaximin is an antibiotic that fights bacterial infection only in the intestines.
Rifaximin works differently from other antibiotics because it passes through your stomach and into your intestines without being absorbed into your blood stream. Because rifaximin treats only the intestinal tract, it will not treat infections of other parts of the body.

Rifaximin is used to treat travelers' diarrhea caused by E. coli in adults and children who are at least 12 years old. Most people get this infection by eating food or drinking fluids that have been contaminated with the bacteria.

Rifaximin is also used to lower the risk of worsened brain function, or hepatic encephalopathy (he-PAT-ik en-SEF-a-LOP-ath-ee), in adults with liver failure. Brain function can be affected when the liver stops working and cannot remove toxic substances from the body.
Rifaximin may also be used for other purposes not listed in this medication guide.

What are the possible side effects of rifaximin (Xifaxan)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Stop using rifaximin and call your doctor at once if you have a fever or diarrhea that is watery or bloody.
Less serious side effects are more likely, and may include:
  • bloating, gas, stomach pain;
  • feeling like you need to empty your bowel urgently;
  • feeling like your bowel is not completely empty;
  • nausea, vomiting, constipation;
  • headache, dizziness;
  • tired feeling; or
  • swelling in your hands, feet, or torso.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the most important information I should know about rifaximin (Xifaxan)?

Rifaximin works differently from other antibiotics because it passes through your stomach and into your intestines without being absorbed into your blood stream. Because rifaximin affects only the intestinal tract, it will not treat infections of other parts of the body.
You should not use take this medication if you are allergic to rifaximin or medications such as rifabutin (Mycobutin), rifampin (Rifater, Rifadin, Rifamate), or rifapentine (Priftin).
Before you take rifaximin, tell your doctor if you have severe liver disease, diarrhea with fever, or diarrhea that is watery or has blood in it.
Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Rifaximin will not treat a viral infection such as the common cold or flu, or any form of diarrhea that is caused by a virus.
Call your doctor if your symptoms do not improve after 24 hours, or if they get worse while taking rifaximin. Rifaximin does not treat all bacterial forms of traveler's diarrhea.






What should I discuss with my healthcare provider before taking rifaximin (Xifaxan)?

You should not use take this medication if you are allergic to rifaximin or medications such as rifabutin (Mycobutin), rifampin (Rifater, Rifadin, Rifamate), or rifapentine (Priftin).
If you have any of these other conditions, you may need a rifaximin dose adjustment or special tests:
  • severe liver disease;
  • diarrhea with a fever; or
  • watery or bloody diarrhea.
FDA pregnancy category C. It is not known whether rifaximin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.
It is not known whether rifaximin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take rifaximin (Xifaxan)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Rifaximin can be taken with or without food.
Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Rifaximin will not treat a viral infection such as the common cold or flu, or any form of diarrhea that is caused by a virus.
Call your doctor if your symptoms do not improve after 24 hours, or if they get worse while taking rifaximin. Rifaximin does not treat all bacterial forms of traveler's diarrhea.
Store at room temperature away from moisture and heat.

Xifaxan Patient Information including If I Miss a Dose

What happens if I miss a dose (Xifaxan)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Xifaxan)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking rifaximin (Xifaxan)?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking rifaximin and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

What other drugs will affect rifaximin (Xifaxan)?

There may be other drugs that can interact with rifaximin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about rifaximin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
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Here is another article...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815818/

Yonsei Med J. 2005 Jun 30; 46(3): 399–407.
Published online 2005 Jun 30. doi:  10.3349/ymj.2005.46.3.399
PMCID: PMC2815818

Comparison of Rifaximin and Lactulose for the Treatment of Hepatic Encephalopathy: A Prospective Randomized Study

INTRODUCTION

Hepatic encephalopathy (HE) is presented clinically as a combination of neuropsychiatric abnormalities characterized by alterations in mental status, personality, intellectual function, and changes in neuromuscular activity. It is frequently observed in those with both acute liver failure and liver cirrhosis.1The pathogenesis of the syndrome is complex, but ammonia produced by intestinal bacteria is known to play an important role in its pathogenesis. The treatment of HE has focused on reducing both the production and absorption of gut-derived ammonia. Presently, non-absorbable disaccharides and antibiotics are the mainstay of therapy.2,3 However, currently used drugs have several limitations. For example, neomycin, a poorly-absorbed aminoglycoside may cause nephrotoxicity and ototoxicity,3 and lactulose treatment may be complicated by excessive diarrhea and abdominal pain.4,5
Rifaximin (4-deoxy-4'-methylpyrido-(1',2'-1,2)-imidazo-(5,4C)-rifamycin SV) is a derivative of rifamycin, which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. Rifaximin is virtually unabsorbed after oral administration and exhibits broad spectrum antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative microorganisms within the gastrointestinal tract.6 During the past decade, several European studies have proved the efficacy of rifaximin for the treatment of HE in Caucasian patients.7-14 However, no similar investigation has been performed in Asian patients.
It has been reported that ethnicity can affect therapeutic response to anti-viral therapies and the long-term prognosis of patients with advanced liver diseases.15-17 In particular, it is not known whether ethnic background affects the effectiveness of rifaximin in the treatment of HE. In Korea, hepatitis B is the major cause of decompensated liver cirrhosis presenting hepatic encephalopathy, in contrast, in Western countries, liver cirrhosis secondary to alcohol abuse predominates.18,19 Alcohol overdose often leads to intestinal bacterial overgrowth which is one of the important precipitating factors of HE.20 Thus etiologic differences may affect the therapeutic efficacy of rifaximin in Korean patients with HE. Therefore, we conducted this prospective, randomized study to determine the efficacy and tolerability of rifaximin versus lactulose for the treatment of HE in Korean patients.

MATERIALS AND METHODS

Patients

Sixty-four in-patients with episodic HE who were admitted at Yonsei University Medical Center (Seoul, Korea) were firstly enrolled in the study. All patients were affected by decompensated liver cirrhosis and HE, which were diagnosed based on clinical and laboratory findings. Patients showed signs of the first to third degree HE, according to Conn's modification of Parsons-Smith classification,21 and had serum ammonia levels > 75 µmol/L.
The criteria for exclusion from the study were: an age <18 years, the presence of a major neuropsychiatric illness, presence of intestinal obstruction or inflammatory bowel disease, hypersensitivity to rifamycin or disaccharides, a serum creatinine level>twice normal, those that had received loop diuretics, antacids or cathartics within the 12 hour period preceding study commencement, patients that were on antibiotics during the preceding 7 days, and those that had been treated with encephalopathy-causing agents. Women of child-bearing age were excluded if they were not using a method of contraception.
Ten of the 64 initially enrolled patients were excluded, and 54 patients finally entered the trial. The enrolled patients were 37 males and 17 females, aged between 40 and 71 (mean age 55.7 years). At the start of the study, the demographic and clinical parameters of the patients in the two groups showed no significant differences (Table 1). Identified precipitating factors included dehydration (n=14), protein overload (n=13), constipation (n=12), bacterial infection (n=3), and unknown (n=12). There was no significant difference between the two groups in terms of factors precipitating HE (Table 2).
Table 1
Clinical and Laboratory Characteristics of the Patients
Table 2
Hepatic Encephalopathy Related Factors of the Patients
The research was performed in accordance with the revised Helsinki Declaration, and the study protocol adopted was approved by the Yonsei University Medical Center Institutional Ethics Committee. The protocol was explained to at least one relative of each patient selected for the study, and written informed consent was obtained from all patients who participated or from their relatives.

Drug Administration

Using a computer-generated sequential 3:2 block randomization list, patients were assigned to receive rifaximin (Normix®, Alfa Farmaceutici SpA, Bologna, Italy) at 1200 mg per day in three divided doses (n=32) or lactulose (Duphalac syrup®, Choongwae Pharmaceutical, Seoul, Korea) at 90 mL a day (n=22). The treatment duration was 7 days unless symptoms worsened or serious side effects occurred. All patients were given a nutritious diet containing a maximum of 40g of protein per day. At the beginning of the trial, patients underwent a full assessment, including a detailed history taking, and physical and neurological examinations. The following parameters were evaluated before and at the end of the treatment period: complete blood count, blood chemistry, serum electrolytes, renal function, blood sugar, and urinalysis. Adverse events were assessed by the investigators. Any abnormal clinical or laboratory findings observed during the trial were monitored and documented. Drug administration was discontinued in the event of 1) severe side effect, 2) taking any medication that could potentially interfere with the course of HE, 3) a serious cirrhotic complication such as acute variceal bleeding, or spontaneous bacterial peritonitis, and 4) a patient's refusal to participate in the trial.

Grade of mental state

This was examined semi-quantitatively using Conn's modification of the Parsons-Smith classification.21Grade 0: no abnormality; Grade 1: trivial loss of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction performance; Grade 2: lethargy, disorientation with respect to time, obvious personality change, inappropriate behavior; Grade 3: somnolence to semi-stupor, responsive to stimuli, confusion, gross disorientation, bizarre behavior; and Grade 4: coma, unable to test mental function.

The severity of flapping tremor

Severity was determined by extending the patients' arms and forearms with the wrists dorsiflexed for at least 30 seconds. We adopted a simplified grading system to minimize inter-observer variance. Grade 0: no flapping motion; Grade 1: infrequent flapping motion; Grade 2: continual flapping motion; and Grade 3: unable to test.

Number connection test (NCT)

The time taken to connect 25 progressive numbers, i.e. part A of the number connection test.22,23 Grade 0: < 30 sec (normal); Grade 1: 31-50 sec; Grade 2: 51-80 sec; Grade 3: 81-120 sec; and Grade 4: > 120 sec.

Blood ammonia levels

Blood ammonia was measured before and after the treatment using Cobas Integra 800 (Roche, Basel, Switzerland). Grade 0: < 75 µM/L; Grade 1: 76-150 µM/L; Grade 2: 151-200 µM/L; Grade 3: 201-250 µM/L; and Grade 4: > 251 µM/L.

HE index

The above items were determined before treatment and on days 3, 5, 7 of the trial period. The grades for the above four components were weighted in proportion to their importance. Thus, HE grade awarded a weighting factor of three, while the other variables were each assigned a factor of one. The HE index was defined as the total of the weighted grades, and had a possible range of 0 to 23 points, i.e., HE index=(grade of mental state) × 3+(grade of number connection test)+(grade of flapping tremor)+(grade of blood ammonia).21

Efficacy of treatment

Efficacy was graded as 'improved', 'unchanged', or 'worsened'. A decrease of HE index by at least one point was defined as 'improved', and increment of the HE index by one point or more was defined as 'worsened'.

Statistical analysis

All data are expressed as means±SD. Statistical evaluations were performed using SAS version 6.12 for Windows (SAS Institute Inc., Cary, NC). Statistical analyses were made using the Student's T-test, the paired T-test, Fisher's exact test, and the Chi-square test. This study satisfied a statistical power of 0.8. A probability level of p < 0.05 was considered to be significant throughout.

RESULTS

Comparison of therapeutic responses to rifaximin and lactulose

Table 3 compares the therapeutic effects of rifaximin and lactulose. Mean blood levels and grades of blood NH3 significantly decreased with both rifaximin (p < 0.01) and lactulose treatment (p × 0.01). Mean blood NH3 concentrations were similar after both forms of therapy (Fig. 1A). Mental state was significantly improved by rifaximin (1.3→0.3) and by lactulose (1.5→0.5) (p < 0.01 and p < 0.01, respectively). Grades of flapping tremor and NCT were improved to nearly equal degrees by rifaximin and lactulose treatment (Table 3). Mean HE indexes improved both in the rifaximin group (10.0→4.2, p=0.000) and in the lactulose group (11.3→5.0, p=0.000) (Fig. 1B). No significant difference was found between the two groups in terms of the grades of HE components at any given time.
Fig. 1
(A) Changes in grade of blood ammonia level with Rifaximin (solid line) or Lactulose (dotted line) treatment. Grade of blood ammonia was significantly decreased at the end of the treatment with respect to pre-treatment values in both groups (p < ...
Table 3
Changes in HE Index and HE-related Parameters after Treatment

Clinical efficacy

At the completion of treatment, blood NH3 and HE grades improved in 25 (78.1%) and 26 (81.3%), respectively, of the 32 patients in the rifaximin group. In the lactulose group, 13 (59.1%) of the 22 patients showed reduced blood ammonia grades and 16 cases (72.7%) improved HE grades. These group differences were not statistically significant (Table 4). Clinical efficacy was determined using HE index improvement. Rifaximin was considered effective in 27 of 32 patients (84.4%) and lactulose in 21 of 22 patients (95.4%), which was not significantly different (p=0.315) (Table 4).
Table 4
Summary of Changes in HE Index, Blood Ammonia and HE Grade after Rifaximin or Lactulose Treatment in Patients with HE
We then compared the clinical characteristics of patients who showed a HE index improvement (n=27) with those who did not (n=5) after rifaximin treatment (Table 5). No significant differences in terms of age, sex, cause of liver disease, Child-Pugh class, episode of HE, or baseline mental state was observed between the two groups. Baseline blood urea nitrogen and creatinine levels were higher in patients who showed HE improvement after rifaximin treatment. Interestingly, the baseline ammonia level and the HE index were higher in the improvement group than in the no-improvement group after rifaximin treatment (p < 0.05) (Table 5).
Table 5
Comparison of Clinical Parameters between the Patients who Showed Improvement of HE and those who Did not after Rifaximin Treatment

Adverse effects

Overall patient compliance was excellent. One patient treated with rifaximin complained of abdominal pain, and one patient treated with lactulose experienced severe diarrhea, but no patient was withdrawn from the trial due to an undue adverse effect. Renal function impairment did not occur in any patient.

DISCUSSION

Although a number of other possible factors have been proposed to play a role in the pathogenesis of HE, such as, the production of central benzodiazepine agonists, endogenous opioids and false neurotransmitters, ammonia is still viewed as the key contributor.2 Thus the mainstay treatment for HE revolves about reducing the production and absorption of ammonia in the gut, and to improve its excretion by drug therapy or diet modification. Currently, lactulose and nonabsorbable antibiotics are most commonly used therapeutics to treat HE.1-3 Several placebo-controlled trials of lactulose have reported no proof of superiority versus a placebo. However, these negative results are believed to be due to the designs of trials, variables of efficacy, and to low numbers of enrolled patients.24-27 Lactulose is currently recommended as the first-line pharmacological treatment for HE by the practice guidelines proposed by the American College of Gastroenterology.28 However, the use of lactulose may be associated with nausea, flatulence, abdominal cramps, severe diarrhea, and dehydration.4,5,29 Protracted diarrhea may result in hypertonic dehydration with hypernatremia, which may aggravate the patient's mental state.30
Antibiotics are regarded as a therapeutic alternative to nonabsorbable disaccharides for HE treatment.28Neomycin is a non-absorbable aminoglycoside that has also been prescribed for HE, but its ototoxicity and nephrotoxicity limit its use in HE.3 Metronidazole, which differs from neomycin in terms of its bacterial spectrum, also improves HE, however its potentially severe neurotoxicity in patients with cirrhosis limits its common use.31 Rifaximin is a semi-synthetic derivative of rifamycin, has broad-spectrum antimicrobial activity,6 and is characterized by its non-absorbability by the gut.32 Rifaximin remains in high concentrations in its active form in the gut and is excreted in feces without causing significant systemic side effects such as nephrotoxicity.6 Moreover, Rifaximin has been shown in previous studies to be effective at reducing HE parameters in cirrhotics.7-14 However, most reports on this subject have emanated from Europe. It has also been reported that combinatorial rifaximin and lactulose is superior to combined neomycin and lactulose for HE treatment.8 In addition, a recent randomized, controlled study conducted in Spain found that rifaximin and lactitol, a nonabsorbable disaccharide, have similar efficacies for the treatment of acute HE.14
The present study is the first, prospective randomized study to compare the efficacy of rifaximin with that of lactulose for the short-term treatment of HE in Asia. No data is available upon whether ethnic background affects the effectiveness of rifaximin for the treatment of HE. Our study confirms that rifaximin is as effective as lactulose for the treatment of HE in Korean patients. Administration at 1200 mg per day led to an objective and significant improvement in mental state, blood ammonia levels, and HE index. Moreover, no significant difference was found between rifaximin and lactulose in terms of their efficacies. These results suggest that ethnic differences do not significantly affect the efficacy of rifaximin as a HE treatment. In this study, the fact that hepatitis B virus is the predominant (75.9%) cause of HE should be considered. In Western countries, alcoholic abuse remains the most common etiology of liver cirrhosis with HE.18,19 Considering intestinal bacterial overgrowth due to alcohol,20 rifaximin might theoretically be a better choice in alcoholic HE than in viral hepatitisrelated HE. However, our results are similar to those of Western studies concerning the efficacy of rifaximin for the treatment of HE, which suggests that the cause of HE is of secondary importance when considering rifaximin as a therapeutic regimen for HE.
When we analyzed the clinical parameters of patients who showed an improvement with those who did not after rifaximin treatment, several factors were found to be significant by univariate analysis. However, limited patient numbers prevented multivariate analysis. We believe that further study of a larger number of patients would be necessary to identify those factors that determine responsiveness to rifaximin in HE treatment. Interestingly, mean baseline ammonia level and HE index were higher in the improvement group than in the no-improvement group after rifaximin treatment, which suggests that rifaximin can be a first-line choice for the treatment of moderate to severe grade HE.
The identification and correction of factors precipitating HE is of primary concern during the management of HE,29 because the correction of such factors usually results in improvement. Thus patients' precipitating factors should be carefully considered in any future trial. In our study, most patients had an identifiable precipitating factor, and the two treatment groups had reasonably similar precipitating factors profiles. Therefore, we believe that any potential bias caused by precipitating factors was minimal in the present study. Rifaximin was also fairly well tolerated; only one patient experienced abdominal pain attributed to the drug. Renal toxicity and other serious side effects were absent, and no ethnically distinct side effects were observed.
All HE therapeutic trials can be criticized from the perspective of evidence-based medicine.33 Criticisms include the definitions of study endpoints, the treatment of control groups, the proper quantification of therapeutic effects. Sanaka et al. prudently described the difficulties of designing good HE treatment tirals.34 The mental status evaluation system using the portal systemic encephalopathy (PSE) index developed by Conn et al.21 is currently widely used. However, the Food and Drug Administration (FDA) strongly objected to the use of this system and favoured the adoption of a detailed mental status evaluation system for HE.34
Although the present study has a limitation due to its being an open-label study, and may not overcome some of the challenges previously mentioned, it shows that rifaximin is as safe and as effective as lactulose in Korean patients with HE. Rifaximin offers a useful therapeutic option in Asian patients with HE who are unable to tolerate treatment with disaccharides or who have an impaired renal function. Further clinical trials using a new mental state evaluation system, which satisfies the FDA's requirements is required to confirm the efficacy of rifaximin for the treatment of HE.

ACKNOWLEDGEMENTS

The authors thank Ajou Pharmaceutical, Co. Ltd. (Kyunggi-do, Korea) for supplying the rifaximin tablets and lactulose. We also thank Suk Hwa Yoon, RN for technical assistance and data collection.

Footnotes

This research was supported by a grant from Ajou Pharmaceutical, Co. Ltd. (Kyunggi-do, Korea) who also provided the rifaximin and lactulose.

References

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26. Watanabe A, Sakai T, Sato S, Imai F, Ohto M, Arakawa Y, et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology. 1997;26:1410–1414.[PubMed]
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Articles from Yonsei Medical Journal are provided here courtesy of Yonsei University College of Medicine

Monday, December 18, 2017

Metformin and Liver Cirrhosis... Could there be a Connection?

Today, I spoke to a woman who told me she doesn't know how she got her cirrhosis. And she has been taking Metformin, for diabetes, for many years.

Now, if this was the first person I'd ever talked to, who told me this, I might think nothing of it. But I've had so many people tell me they couldn't figure out how they got their cirrhosis.... and they just happened to be taking Metformin... 

Things that make you go, HMMMM!

Today was that day I finally got around to looking into this a little further. 

She did say that she had a lot of dental work done. And I told her that my husband experienced liver problems after getting dental work done, because a liver with fibrosis (even if it's not CIRRhosis) can react poorly to the anesthesia you get in a dental chair.  She said yes, she'd had dental work done. So I am guessing that is a contributing factor. 

Then, my next call was with a woman who just got a water machine this weekend. She called to tell me that her Dad looked more clear headed than she's seen him in a long time, and her Mom (who is also on Metformin) agreed. Her Mom has had a lot of health issues also.

OK so here is my OPINION on the whole Metformin thing.

In my OPINION, metformin may cause more liver toxicity, than people realize, especially when it's taken for extended periods of time. And it's taken by someone with Diabetes, who is already struggling with health issues.  People with type 2 diabetes would usually, greatly benefit from a change in their diet, and may already have a certain amount of liver issues that have steadily been building, for several years (the liver can take a LOT of damage, until all of a sudden, it's like.... glaring loud warning signals like a fire alarm going off).

So, it doesn't really surprise me that people on Metformin will gradually start having a LOT of different health issues. When you rely on taking lots of medications, to fix your health issues, without changing your diet... it's just like a guaranteed recipe for disaster. 

I'd read once, that ALL prescription medications are toxic to the liver, to some degree, and I believe it. The problem is that doctors make it sound like it's NORMAL for a person to be on medications, for the rest of their lives. And I truly believe that if doctors made NO MONEY whatsoever, from prescriptions... it would be an entirely different story.  Kickbacks for prescription medications should be ILLEGAL.

Below is some info I pasted from this page.... decide for yourself.
Maybe the instance is low, but... somehow, these people and their relatives manage to keep finding my blog!

https://www.livestrong.com/article/245459-metformin-effects-on-the-liver/ 





Mild Liver Dysfunction

According to LiverTox, a publication of the U.S. National Library of Science drug database, Metformin may occasionally cause mild liver toxicity, characterized by minor elevations in liver enzymes. It occurs in less than 1 percent of the patients taking Metformin and usually appears within the first one to eight weeks of treatment, according to LiverTox. Liver problems usually resolve quickly once you stop taking the Metformin, according to LiverTox.

Knowing the Signs

Your liver is a critical organ that is responsible for detoxifying your blood. While Metformin influences the liver in some positive ways that result in decreased glucose output, it's capable, under rare circumstances, of negatively affecting liver function. Seek immediate medical attention if you notice signs of liver toxicity, which include weakness, fatigue or jaundice.


is some info I pasted from this page:

 https://livertox.nlm.nih.gov/Metformin.htm



OVERVIEW
Metformin

Introduction

Metformin is a first line agent for the treatment of type 2 diabetes that can be used alone or in combination with sulfonylureas, thiazolidinediones or other hypoglycemic agents.  Metformin has not been linked to serum enzyme elevations during therapy and is an exceeding rare cause of idiosyncratic clinically apparent acute liver injury.


Background

Metformin (met for' min) is a biguanine and acts as an insulin sensitizing agent, probably through activation of adenosine monophosphate dependent (AMP) kinase in liver and muscle tissue.  Metformin is often associated with weight loss making it a preferred, first line agent for management of overweight patients with type 2 diabetes.  Initial concerns about the possibility that metformin (like the related biguanine phenformin) could induce lactic acidosis have been largely resolved, although the agent is contraindicated in patients with renal dysfunction because of this reason and should be used with caution in patients with significant liver disease.  Metformin was approved for use in the United States in 1995 and is currently one of the most commonly used drugs for the therapy of diabetes, with more than 30 million prescriptions filled in the United States yearly.  Metformin is available in many generic forms in tablets of 500, 850 or 1000 mg, the recommended regimen being to start with 500 or 850 mg once daily and increase based upon tolerance to 1000 to 2550 mg daily taken in two divided doses.  Commercial formulations include Glucophage, Glumetza, Fortamet and Riomet.  Metformin is also available in extended release formulations and in combinations with sulfonylureas such as glipizide (Metaglip) or glyburide (Glucovance), DDP-4 inhibitors such as alogliptin (Kazano), linagliptin (Jentadueto), saxagliptin (Kombiglyze) and sitagliptin (Janumet), as well as thiazolidinediones such as pioglitazone (Actoplus) and rosiglitazone (Avandamet).  Metformin is generally well tolerated but side effects can include diarrhea, gastrointestinal upset, abdominal pain, nausea, weakness, headache, dizziness and rash.


Hepatotoxicity

Minor enzyme elevations have been reported to occur during metformin therapy in less than 1% of patients.  Indeed, metformin may actually lower elevated aminotransferase levels in patients with fatty liver disease.  Clinically apparent liver injury from metformin is very rare, fewer than a dozen cases having been described in the literature despite widespread use of this agent for several decades.  The liver injury usually appears after 1 to 8 weeks, typically with symptoms of weakness and fatigue followed by jaundice.  Various combinations of hepatocellular and cholestatic injury have been described, and many have been mixed.  Allergic manifestations are not typical but rash, fever and eosinophilia have been described.  Autoantibody formation is also not typical.  Because this agent is usually given in combination with other hypoglycemic agents, many of which also cause liver injury, it can be difficult to establish whether the injury is due to metformin or another agent.  The timing of injury is perhaps most characteristic, the injury arising soon after the agent is started and not during long term therapy.  Recovery is usually rapid after metformin is stopped.


Mechanism of Injury

The mechanism of liver injury due to metformin is unknown.  Metformin may actually be beneficial for some forms of liver disease, such as nonalcoholic steatohepatitis and need not be avoided in patients with mild, preexisting serum enzyme abnormalities.  Acute liver injury from metformin may have a metabolic basis, arising after weeks to months of therapy.  Rechallenge can lead to recurrence, but also requires weeks to months of therapy before injury reappears.


Outcome and Management

The liver injury from metformin usually resolves rapidly once the agent is stopped.  Chronic injury has not been described.  No convincing cases of fulminant hepatic failure from metformin have been reported.  In cases in which multiple hypoglycemic agents were being used when the liver injury appears, rechallenge with the agent least likely associated with the injury is appropriate.  There is no cross reactivity in hepatotoxicity with other antidiabetic medications.


Drug Class:  Antidiabetic Agents

 

Top of page


CASE REPORTS 
Metformin

Case 1.  Acute hepatitis due to metformin.
[Modified from:  Deutsch M, Kountouras D, Dourakis SP. Metformin hepatotoxicity. Ann Intern Med 2004; 140: 408-9. PubMed Citation]

 

A 67 year old woman with diabetes was started on metformin (500 mg twice daily) and developed fatigue, weakness and jaundice five weeks later.  She had no history of liver disease or risk factors for viral hepatitis and did not drink alcohol.  She had coronary artery disease and medications taken chronically included aspirin, isosorbide mononitrate, diltiazem and acarbose.  On admission, 6 weeks after starting metformin, she had a total bilirubin of 4.8 mg/dL (Table).  Tests for hepatitis A, B and C were negative.  She had antinuclear antibodies (1:320).  An abdominal ultrasound and CT scan were normal.  Liver biopsy showed acute inflammation.  Metformin and acarbose were withdrawn and gliclazide started. The jaundice slowly resolved over the next three months, but metformin was subsequently restarted, and jaundice reappeared 3 months later.  Metformin was again withdrawn and her liver injury improved slowly.


Key Points

Medication:Metformin (500 mg twice daily)
Pattern:Hepatocellular (R=26)
Severity:3+ (hospitalization for jaundice)
Latency:5 weeks
Recovery:Complete within 2 months
Other medications:Acarbose, diltiazem, aspirin, isosorbide mononitrate

Laboratory Values

Time After StartingTime After StoppingALT* (U/L)Alk P (U/L)Bilirubin* (mg/dL)Other
6 weeks09051214.8ANA: 1:320
7 weeks1 week960
4.5Liver biopsy
8 weeks2 weeks1160
3.0
9 weeks3 weeks1080
3.0
3 months6 weeks280
4.0
4 months10 weeks120


12 weeks40
1.0
Metformin restarted approximately 4 months later
12 weeks0880
3.0
13 weeks1 week1240
2.5ANA still present
14 weeks21120
2.2
15 weeks3920
2.1
4 months4800
2.5
5 months9480
1.0
6 months1340
1.0
Normal Values<40<130<1.2

* Values of ALT and bilirubin were estimated from the figure and converted from times upper limit of normal to absolute values based upon normal values provided.


Comment

This patient developed an acute hepatitis-like illness with mild jaundice after 5 weeks of therapy with metformin which was somewhat slow to resolve.  Upon rechallenge, there was a recurrence of the liver injury, but only after metformin had been given for several months.  Nevertheless, the pattern and subsequent course of the liver injury was similar to the original episode making it likely that metformin was the cause of the injury.  While most causes of liver injury were excluded (hepatitis A, B and C, cholecystitis), the presence of a strongly positive ANA raises the possibility that the patient had autoimmune hepatitis with an acute, fluctuating onset and course.  The liver biopsy apparently did not suggest autoimmune hepatitis, but this possibility can be excluded only by further follow up.  In assessing hepatotoxicity from commonly used medications such as metformin, the possibility of an unusual presentation of a common liver disease must always be considered.


Case 2.  Acute hepatitis-like injury due to metformin.
[Modified from:  Kutoh E. Possible metformin-induced hepatotoxicity. Am J Geriatr Pharmacother 2005; 3: 270-3. PubMed Citation]

 

A 73 year old Japanese woman with poorly controlled diabetes, despite therapy with a sulfonylurea and pioglitazone, was started on metformin (500 mg twice daily) and developed fatigue, weakness and jaundice 3 weeks later.  She was known to have had normal liver tests before starting metformin.  On admission, laboratory testing showed a total bilirubin of 6.5 mg/dL and a hepatocellular pattern of serum enzyme elevations (Table).  All oral antidiabetic agents were stopped and she was managed on insulin.  Tests for hepatitis B and C infection were negative as were autoantibodies.  Ultrasound, CT and ERCP were unremarkable.  Her serum enzymes improved rapidly once metformin was stopped and were normal 7 weeks later.


Key Points

Medication:Metformin (500 mg twice daily)
Pattern:Hepatocellular (R=21)
Severity:3+ (hospitalization for jaundice)
Latency:3 weeks
Recovery:Complete within 2 months
Other medications:Nateglinide and pioglitazone for 6 months

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
Pre
163370.7
3 weeks07726356.5Admission
4 weeks1 weeks3534803.2
6 weeks3 weeks101
2.6Symptoms resolved
8 weeks5 weeks65
1.7
10 weeks7 weeks13
0.6
Normal Values<36<359<1.2

Comment

The patient developed an acute hepatitis-like illness with mild jaundice 3 weeks after metformin was added to a chronic regimen of a metiglinide analogue and thiazolidinedione for poorly controlled diabetes.  Symptoms resolved within 2 weeks and all liver tests were normal 7 weeks after stopping the medications.  No other cause for acute hepatitis was identified.  Both nateglinide and pioglitazone have been reported to cause liver injury, but the timing of onset of the hepatitis most closely implicates metformin.  Rechallenge with the other antidiabetic medications would have been appropriate.