Tarek Saadi

Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review

Introduction Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2). Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database. Case After receiving metformin 850 mg/day for 2 weeks, a 78-year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months. Conclusion Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect.

Secondary antibiotic resistance of Helicobacter pylori isolates in Israeli children and adults

BACKGROUND Failure of standard therapy for Helicobacter pylori infections results primarily from increasing antibiotic resistance. Patients in Israel are referred for H. pylori culture after failure of at least two therapeutic regimens. OBJECTIVES To estimate the prevalence of secondary antimicrobial resistance of H. pylori in Israel. METHODS We retrospectively collected results of H. pylori cultures performed by gastric biopsies at Rambam Health Care Campus, Haifa, Israel, between the years 2012-2015. Antimicrobial susceptibility to five drugs was tested by gradient-diffusion. RESULTS 107 patients, 46 adults and 61 children, were referred for performance of H. pylori cultures. Cultures were positive in 64 samples (63.7%). In adults, 23 (50%) patients had positive H. pylori cultures; 8.69% showed resistance to amoxicillin (AM), 39.1% to clarithromycin (CH), 61.9% to metronidazole (MZ), 8.69% to tetracycline (TC), and 21.7% to levofloxacin (LEV). In children, 41 (67%) patients had positive H. pylori cultures; 5.1% showed resistance to AM, 42.5% to CH, 46.66% to MZ, 2.5% to TC and 0% to LEV. In children, 94.9% of H. pylori strains were susceptible to both AM and LEV. In adults, 82.6% of the strains were susceptible to both AM and TC. 28.6% of adults and 24.1% children were resistant to both MZ and CH. CONCLUSIONS The sensitivity of H. pylori culture was low. Resistance of H. pylori to MZ and CH was very high after failure of two therapeutic regimens in both adults and children. No LEV resistance was detected in children. AM resistance was higher in adults than in children.

Safety of Corticosteroid Treatment in Rheumatologic Patients With Markers of Hepatitis B Viral Infection: Pilot Evaluation Study.

BackgroundImmunosuppressive agents may induce hepatitis B flares. The minimal corticosteroid dose and duration of therapy leading to HBV reactivation is unknown. ObjectiveTo assess whether short-term corticosteroid therapy for rheumatologic diseases induces HBV reactivation. MethodsThe records of all HBsAg or HBcore antibodies positive, anti-HBs negative patients who were hospitalized in the rheumatology department during 2001–2014 and treated with corticosteroids were reviewed. Alanine aminotransferase (ALT), HBV serology, and serum HBV DNA at baseline and 1–3 months after discharge were recorded. ResultsComplete data were found for 23 patients who were hospitalized 73 times for 7 days of treatment with IV corticosteroids. Eighteen patients were HBsAg positive. The mean methylprednisolone dose was 33.9 ± 24 mg/d. The concomitant therapy included DMARDs (15), low-dose corticosteroids (8), and biologicals (10). Serum HBV DNA was detected at baseline in seven patients. Three HBsAg-positive patients treated with cyclophosphamide had HBV hepatitis flare-up with elevated ALT. Two HBsAg-positive patients had reappearance of HBV DNA in serum after treatment with azathioprine and infliximab, respectively, but the ALT levels remained normal. Lamivudine therapy reduced the serum HBV DNA and improved ALT levels in all patients. Corticosteroid therapy by itself did not trigger exacerbation of HBV hepatitis. No HBV reactivation occurred in lamivudine-treated patients after recurrent exposure to biologicals or cyclophosphamide. ConclusionsShort episodes of corticosteroids seem to be safe in HBV carriers, even in the presence of DMARDs, but lamivudine prophylaxis should be considered for patients exposed to biologicals or cyclophosphamide. Larger prospective trials are needed to establish guidelines.

Gaucher's disease type I: a disease masked by the presence of abnormal laboratory tests common to primary liver disease

Gauchers disease (GD) may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy with imiglucerase. GD is associated with cytopenia, bone complications, hepatosplenomegaly, hypermetabolism, and hyperactivity of the immune system manifested by polyclonal hyper gamma-globulinemia and an increased incidence of monoclonal gammopathies. High ferritin and presence of autoimmune antibodies may present and because of these abnormalities, clinical similarities with primary liver diseases may occur. We report on two patients who suffered diagnostic delay that could potentially lead to life-threatening manifestations of GD. Potential complications include: avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, and liver pathology. Physician awareness will increase the likelihood of prompt detection of GD and improve its management.

Severe hyperferritinemia—a clue for severe hepatitis in a patient with adult-onset Still’s disease

A 19-year old previously healthy man developed the adult-onset Still’s disease (AOSD) with high ferritin levels. Corticosteroids induced clinical remission with resolution of fever, arthritis, and rash. While tapering corticosteroids, the patient developed severe liver enzymes elevation, very high ferritin levels and, subsequently, acute liver failure. After other causes of liver disease (infections, metabolic, autoimmune hepatitis, lymphoma, and hemophagocytosis) were excluded, severe hepatitis was attributed to AOSD itself. Cyclosporine induced rapid normalization of liver enzymes and reduction in ferritin levels. Severe hepatitis and very high ferritin levels could be the only manifestation of disease activity in AOSD; therefore, monitoring of liver enzymes and ferritin levels is recommended even after resolution of the clinical symptoms of AOSD. Prompt initiation of cyclosporine can improve liver function and prevent progression to liver failure.

spontaneous bacterial peritonitis with a very high leukocyte count in ascitic fluid caused by Haemophilus influenzae

We report on a case of spontaneous bacterial peritonitis (SBP) due to Haemophilus influenzae (H. influenzae) in an elderly patient with alcoholic cirrhosis. The patient presented with a 5 day history of fever, cough, and fatigue. Abdominal paracentesis revealed a very high neutrophil count (134,800 cells/μL). Secondary peritonitis and abdominal abscess were ruled out. Peritoneal fluid culture displayed the growth of H. influenzae. The patient was treated with ceftriaxone and showed signs of improvement. Eventually, the patient died due to septic shock caused by other organisms. H. influenzae is a very rare cause of SBP. This case report demonstrates that (1) H. influenzae should be considered a potential cause of SBP, and (2) a very high leukocyte count in ascitic fluid can be found in patients with SBP.

Severe Elevation of Liver Enzymes Does Not Necessarily Require Treatment Interruption in Patients Treated With a Combination of Paritaprevir/Ritonavir/Ombitasvir Plus Dasabuvir for HCV Infection.

To the Editor: Drastic advancements have been made in the treatment of chronic Hepatitis C virus (HCV) infections over the past 2 decades. The use of direct-acting antiviral (DAA) agents against HCV infections can result in the successful treatment of nearly all patients. Adverse events are generally mild.1 We report a 46-year-old female patient with chronic HCV infection genotype 1b and fatty liver disease. During the first weeks after beginning treatment with a combination of paritaprevir/ritonavir/ombitasvir, dasabuvir (PrOD) and ribavirin, severe elevation of liver enzymes was shown: alanine transaminase 1029U/L, aspartate transaminase 365U/L, total bilirubin 1.7mg/ dL and direct bilirubin 0.7mg/dL, normal ALKP and GGT. The patient was asymptomatic. Thorough investigation was negative and the elevation of the liver enzymes was attributed to the antiviral therapy. Close follow-up allowed us to complete the antiviral therapy and sustained virological response (SVR) was achieved. Liver enzymes improved significantly after the eighth week of treatment. In the current era of HCV therapy with DAA combination regimens, successful treatment is achievable in nearly all infected patients with limited toxicity. In real life, we can encounter special cases. In this report, we presented a case of advanced liver disease due to chronic infection with HCV. On the one hand, we aim to reach SVR and, on the other hand, we are concerned about the side effects of these drugs, especially after reports of the risk of hepatic decompensation with these drugs. Marked elevations in liver enzymes during treatment with DAAs are infrequent (r1% in the overall population), but are more prevalent among females using medications containing ethinyl estradiol. In most cases, the rise in alanine aminotransferase was transient and resolved without study drug interruption. Owing to the inhibition of bilirubin transporters by paritaprevir, elevations in unconjugated bilirubin can be seen upon initiation of PrOD therapy. Bilirubin elevations typically peaked within the first week, were not associated with serum alanine aminotransferase elevations, and did not result in any treatment discontinuations.2,3 In this case, the elevation of liver enzymes was severe but the patient was asymptomatic. Close follow-up allowed us to complete antiviral treatment and to achieve SVR. In summary, severe elevation of liver enzymes can occur during treatment with PrOD in patients with chronic HCV infection. Fatty liver disease can be a risk factor for this side effect. Close follow-up can allow us to complete antiviral therapy and does not necessarily require treatment interruption.

Recurrent small intestinal ileus secondary to valsartan treatment.

To the Editor: Angiotensin receptor blockers (ARBs) are generally considered safe and well tolerated and are associated with superior compliance in comparison with other antihypertensive drugs.1,2 Recently, the Food and Drug Administration reported an adverse effect of ARB, namely olmesartan. Several cases of olmesartan-associated sprue-like enteropathy were reported. Herein, we report on a patient with recurrent small bowel ileus secondary to valsartan treatment. A 57-year-old man, a physician, was hospitalized with 3 days of diffuse severe abdominal pain. He reported having several similar episodes during last year. Each episode lasted 5 to 7 days. His complains included abdominal distension, nausea, and constipation. He denied fever, vomiting, or diarrhea. He had no history of abdominal surgery, abdominal trauma, or episodes of bowel obstruction. He reported feeling well between the episodes. His past medical history was significant for essential hypertension and hyperlipidemia. He was treated by pravastatin 20mg/d (started 5 y ago) and valsartan 160mg/d (started 2 y ago). On physical examination, diffuse abdominal tenderness and attenuated bowel sounds were found. Blood tests were normal, including complete blood count, liver enzymes, renal function, electrolytes, amylase, and lactic acid levels. Imaging studies demonstrated small bowel obstruction with dilatation of the proximal jejunum, duodenum, and the stomach. Laparotomy was performed, but no mechanical obstruction was found. He was treated conservatively and his complains resolved completely. After 5 days the patient was discharged. During the subsequent year, the patient was admitted 3 more times with the same clinical picture. At each episode he was treated conservatively with NPO and intravenous fluids, with symptoms usually resolving after 5 to 7 days. A thorough investigation was carried out and included upper endoscopy, colonoscopy with ileoscopy, and push enteroscopy, all found to be normal. Imaging studies did not reveal any abnormalities that could explain recurrent obstructions. Biopsies from the stomach, duodenum, jejunum, ileum, and the colon were normal. One year after the onset of symptoms, valsartan was discontinued by the patient because of unknown reason. Since the discontinuation of the medication, the patient’s symptoms completely resolved. At 1 year of follow-up, he feels well, without any abdominal pain, obstructive symptoms, or other gastrointestinal complaints. As ARBs do not involve angiotensin converting enzyme inhibition but specifically antagonize the action of angiotensin II at its angiotensin 1 (AT1) receptor site, this drug class would be anticipated to be devoid of the characteristic ACE-inhibitors– associated side effects.3,4 Valsartan has been studied in >100,000 patients and has demonstrated good tolerability across broad patient populations with an adverse event profile of ARBs, which was found to be similar to that observed with placebo.1,5,6 No significant gastrointestinal effects of valsartan were reported. We believe that there is a direct association between valsartan and the clinical picture. We hypothesize that the potential mechanism could be related to the presence of angiotensin receptors on the intestinal mucosa. The effect of angiotensin on bowel motility was suggested by animal models, whereby angiotensin II regulates intestinal motility in guinea pigs7 and angiotensin receptors occur in the mucosa and muscularis layers of the jejunum and ileum as well as the colon in rats.8 Novel data from human esophagus and jejunum suggest that AT(1) receptor mediates muscular contractions and that AT(2) receptor regulates epithelial functions.9 The effect on contractility of angiotensin II was also shown in the mouse colon, whereas losartan antagonized this effect.10 These findings underscore the positive promotile effect of angiotensin II on the small and large intestine and the potential for angiotensin II receptor antagonists in blocking this effect. However, reports of ileus or colonic pseudo-obstruction are very sparse. In fact, we could not find any case of significant intestinal pseudoobstruction, and even abdominal bloating does not appear to be a common side effect of ARBs. In summary, we reported an unusual case describing bowel ileus secondary to the use of valsartan, and this is the second case described so far in the literature.11 We believe that patients with chronic or recurrent abdominal pain and other signs of bowel obstruction who receive valsartan with or without other medication that block the renin angiotensin system should be assessed for the role of these medications in causing their symptoms. However, additional cases should be documented before a definite association could be determined.