Prolonged cholestasis associated with short-term use of celecoxib

Drug-induced liver injury due to celecoxib, a first generation Cox-2 inhibitor, has been rarely reported. We describe one case of severe and prolonged cholestasis after treatment with celecoxib for 12 days in a young woman with no evidence of other causes of liver disease or allergy. Jaundice lasted for 3 months, pruritus and abnormal liver biochemistry persisted for 18 months after stopping the drug. Liver biopsy specimens showed a cholestatic pattern of liver injury with only minimal mononuclear infiltrate in the portal tracts. This case report supports the notion that celecoxib may cause bland, long term cholestasis.     

Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes

Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.     

Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5‐year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.     

A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole

Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases.     

A case of sustained cholestasis caused by acute A viral hepatitis in Dubin-Johnson syndrome

Dubin-Johnson syndrome is a rare clinical entity. It shows intermittent symptoms such as chronic or intermittent jaundice, abdominal pain, weakness, nausea, vomiting, anorexia and diarrhea. Symptoms are precipitated or aggravated by pregnancy, alcoholism, surgical procedures and intercurrent disease. Chronic idiopathic jaundice is typical of Dubin-Johnson syndrome and its prognosis is good. We describe a case of prolonged cholestasis for more than 10 months caused by acute A viral hepatitis in a patient with Dubin-Johnson syndrome. It is a first report of cholestasis complicated by acute A viral hepatitis in a patient with Dubin-Johnson syndrome.     

Severe recurrent intrahepatic cholestasis in systemic AL amyloidosis without obvious liver involvement: unexplained hepatic toxicity or a case of misdiagnosed liver amyloidosis?

We report the case of a 50-year-old woman who was admitted to the hospital for acute abdominal pain with nephrotic proteinuria, rapidly progressive renal failure, and moderate anemia. Laboratory tests showed mild Bence Jones (λ) proteinuria with negative serum immunofixation and a mild increase in λ free light chains. A bone marrow biopsy and a fat tissue aspirate showed multiple myeloma and amyloidosis. Because of the end-stage renal disease, the patient began regular dialysis treatment and was started on bortezomib 1.3 mg/m2 plus dexamethasone 40 mg on days 1, 4, 8 and 11 of 21-day cycles. Ten days later she complained of a new episode of abdominal pain with jaundice. A CT scan and an MRI scan ruled out all secondary causes of cholangitis including cancer. Acute intrahepatic cholestasis due to amyloid deposition was then hypothesized. After 4 well tolerated cycles of bortezomib and dexamethasone, blood tests showed a complete hematological response with full reversal of cholestasis. After three months, a new episode of abdominal pain occurred and this time the patient was operated on and found to have an intestinal volvulus. Because of the jaundice, a transjugular liver biopsy was performed showing no evidence of amyloid deposits. Two months later the patient died of septic shock. Although no autopsy was performed and the ultimate cause of the cholestasis could not be ascertained, amyloidosis remains the major culprit in this unfortunate case.     

Single-center experience in management of progressive familial intrahepatic cholestasis

Background and study aimsProgressive familial intrahepatic cholestasis (PFIC) is an autosomal recessively inherited disease that causes intrahepatic-hepatocellular cholestasis. PFIC constitutes approximately 10–15% of cholestatic liver diseases in children. The aim of this study is to draw attention to this group of diseases, which pose a higher risk, in societies where consanguineous marriage is more common, and to share our experiences since the studies in the literature, regarding this group of diseases are case series with small number of patients.Patients and methodsThis cross-sectional study was conducted on 34 patients who were admitted with jaundice and diagnosed by genetic analysis, between January 2015 and July 2020.ResultsWe found 17.6% of patients with PFIC type 1, 55.9% patients had PFIC type 2, 14.7% patients had PFIC type 3, 8.8% patients had PFIC type 4 and 2.9% patients had PFIC type 5. Partial internal biliary diversion was performed in 5 (14.7%) patients, who had severe itching during follow-up, did not respond to medical treatment, and did not have significant fibrosis in liver biopsy yet. The degree of itching before PIBD was rated as +4 (cutaneous erosion, bleeding and scarring), in 5 patients and the rates were 0 (absent) in two patients, and +1 (mild itching) in 3 patients, 6 months after PIBD, these differences were statistically significant(p = 0.027). The mean weight z score was-1.43 (-3.72-+0.73), before PIBD, while it was 0.39(-1.86 -+2.45), six months after PIBD; the diference was statistically significant(p = 0.043). Liver transplantation was performed in 12 (35.3%) patients with significant fibrosis in liver biopsy and developing signs of portal hypertension.ConclusionThe PFIC disease group is a heterogeneous disease group that is difficult to diagnose and treat. It should be considered in patients with cholestasis and/or pruritus and those with a history of consanguineous marriage between parents and death of a sibling with similar clinical symptoms.     

Cholestatic and hepatocellular injury associated with erythromycin esters

A combined cholestatic and hepatocellular injury occurred in nine patients, following therapy with erythromycin estolate (EE) or other erythromycin derivatives. Eight of the nine patients developed jaundice within three weeks after initiation of treatment; pain was one of the main symptoms in five patients while fever and itching were noted in four patients. Symptoms and signs subsided and abnormal tests of liver function returned to normal after withdrawal of the drug. The major histologic finding was cholestasis, but the majority of cases also had evidence of hepatocellular injury of variable severity; one biopsy specimen showed centrilobular necrosis. Ultrastructural findings in one case included changes related to cholestasis as well as hepatocellular injury with striking mitochondrial abnormalities. Our data are compared with those of the literature, with special reference to morphologic features.     

Severe jaundice in Legionnaires' disease: a case with early hepatic biopsy

Although liver tests are frequently disturbed in Legionnaires' disease, jaundice occurs rarely except as a terminal event. The authors report the case of a 68 year-old man with jaundice as a presenting feature of the disease. Jaundice deepened rapidly until death a few days later. Drugs and other causes of cholestasis could be ruled out. An early liver biopsy was performed. The liver was histologically normal except for mitochondrial margination in the hepatocytes. No Legionella could be demonstrated by direct fluorescent assay. These findings suggest that: jaundice in Legionnaires' disease is not related to direct bacterial insult, cholestasis is probably consecutive to endotoxinemia, the mitochondrial margination, a rare histologic finding, could result from Legionnaires' disease. This last point needs confirmation by further studies.     

Influence of bile duct occlusion on the exocrine pancreas in rats

The exocrine pancreas was studied in the rat after both prolonged permanent and transient biliary obstruction. Double ligation, transection, and transposition of the distal end of the bile duct rendered the animal permanently jaundiced, whereas simple ligation led to a transient jaundice followed by restitution within 15-20 days. In permanent cholestasis pancreatic mass and protein, DNA, amylase, and trypsinogen content were increased. Transient cholestasis probably had only transient effects, since no significant changes in pancreatic mass, protein, DNA or enzymes could be found at 3-5 weeks after surgery. The results show that obstructive jaundice with absence of bile flow to the intestine causes enlargement of the pancreas due to parenchymatous hyperplasia and interstitial edema.     

Cholestasis from ticlopidine: two clinical cases

The development of cholestasis during treatment with ticlopidine is an uncommon event in view of the large number of patients to whom this drug is prescribed. We describe the cases of 2 patients who had been treated with ticlopidine for 4 weeks and 2 months respectively. The first patient developed cholestasis with jaundice and pruritus while the second presented with biochemical cholestasis but no jaundice. When treatment with ticlopidine was withdrawn, in the first case pruritus disappeared and jaundice improved. In both cases the liver function tests returned to normal. Both patients were treated with ursodeoxycholic acid which might have an anticholestatic effect in case of hepatotoxicity induced by ticlopidine.     

COVID-19-associated secondary sclerosing cholangitis – A case series of 4 patients

We report a case series of four patients diagnosed with COVID-19-associated secondary sclerosing cholangitis (SSC), a recently described rare late complication of severe COVID-19. Following prolonged stays in the intensive care unit, these patients developed marked sustained cholestasis and jaundice despite clinical improvement. Cholangiography showed beaded appearance of intra-hepatic bile ducts and bile casts were removed in one patient. None of the patients reached normalization of liver enzymes and at least one progressed to liver cirrhosis (follow-up time of 11 to 16 months). COVID-19-associated SSC has a dismal prognosis with rapid progression to advanced chronic liver disease.     

Intrahepatic cholestatic jaundice related to administration of ranitidine. A case report with histologic and ultramicroscopic study

Ranitidine may cause liver injuries ranging from transient, subclinical serum transaminases increase every 100-1,000 treated patients to cholestatic hepatitis in less than 1/100,000. Other H2-receptor antagonists are more dangerous: 11 toxic hepatitis cases have been reported as adverse effect after 1 year of marketed ebrotidine. A 75-year-old male with ischemic cardiopathy history was started on an 8 days treatment of oral ranitidine due to pirosis, without any other changes of therapy; 48 h after drug withdrawal, light-coloured stools, dark urine and icteric scleras developed. On hospital admission, 10 days later, physical examination showed slight hepatomegaly and severe jaundice with skin excoriations followed by serum mixed bilirubin further increase and aminotransferases activities mild rise. Total bilirubin peaked at 381.33 mmol/l (5.1-17.1) and progressively returned to normal, after discharge home, in 3 months and now, 1 year later, there is no sign of liver disease. Ultrasonographic biliary anomalies and the most frequent causes of liver damage were excluded. Liver biopsy confirmed ranitidine as the most likely cause of liver toxicity since histological and ultramicroscopical study revealed a drug-induced picture. We report a rare case of intrahepatic cholestasis jaundice related to ranitidine, a widely used drug. Diagnosis would need an ethically unacceptable rechallange test.     

Cholestatic jaundice associated with the use of metformin

We report a patient who developed cholestatic jaundice shortly after initiation of treatment with metformin hydrochloride. Ultrasound of the liver and abdominal CT were normal. An ERCP showed normal biliary anatomy. A percutaneous liver biopsy was obtained showing marked cholestasis, with portal edema, ductular proliferation, and acute inflammation. Metformin hydrochloride was discontinued, and the patient's jaundice resolved slowly over a period of several months. Given the onset of his jaundice 2 wk after the initiation of metformin, we believe that this case represents an example of metformin-associated hepatotoxicity, the first such case reported.     

Drug-induced jaundice

A large number of drugs may be associated with impaired bile flow. Drug-associated cholestasis presents like other forms of cholestasis with pale stools, dark urine, pruritus and jaundice. Abdominal pain may be present in some instances and can be so severe as to lead to a false diagnosis of acute cholecystitis. Biochemically, drug-associated cholestasis resembles other forms of cholestasis although the presence of eosinophilia may suggest drug involvement. Many types of drug-induced cholestasis run a benign course with resolution of signs and symptoms within 3 months but occasionally the jaundice can take a year or more to resolve. Progression to cirrhosis is uncommon. Some patients may develop a syndrome resembling primary biliary cirrhosis. The mechanisms of drug-associated cholestasis are uncertain but may arise from alteration of bile formation within the hepatocyte or bile excretion at the level of the canaliculus or the extrahepatic ducts. Histological examination of the liver may be helpful in classifying the types of jaundice but the diagnosis of drug-induced cholestasis is usually one of temporal association and exclusion of other causes.     

Cholestatic jaundice induced by D-penicillamine and oral steroid contraceptive in progressive systemic sclerosis (author's transl)

A 25-year-old woman with progressive systemic sclerosis was treated with D-penicillamine. (DPA) 30 days after starting therapy cholestatic jaundice was observed. Moreover, for two years she has taken the pill. Both drugs were discontinued, the jaundice disappeared and the laboratory findings of liver became normal. A rechallenge of D-penicillamine after 9 months induced no reaction. An underlying chronic liver disease before cholestasis could be excluded by liver biopsy. Allergic cutantests and lymphocyte transformation test with D-penicillamine and penicillin gave normal results. The frequency of cholestatic jaundice caused by DPA-therapy is discussed and the possible pathomechanism analyzed.     

Prolonged jaundice following ketoconazole-induced hepatic injury

Two patients developed prolonged and progressive jaundice associated with ketoconazole-induced hepatic injury although the drug was discontinued before or shortly after the onset of symptoms of hepatic toxicity. One patient, who had been jaundiced for eight weeks and was not improving, showed prompt clinical improvement and progressive resolution of jaundice following therapy with prednisolone. Liver biopsy before therapy showed marked cholestasis in all acinar zones and moderately severe fibrosis in the space of Disse. The other patient, who was less severely jaundiced, showed spontaneous resolution although he remained jaundiced for 11 weeks. Liver biopsy performed three weeks after onset of symptoms showed a moderate degree of cholestasis in acinar zone 3 and collagen deposition about the terminal hepatic venules and within the space of Disse. These cases are reported because of the unique clinical course, documentation of the morphologic features, and experience with corticosteroid therapy.     

Hepatitis caused by cyproheptadine (Periactine). A case and review of the literature

We report the case of a patient who developed jaundice after receiving cyproheptadine for 29 days. Complete recovery occurred within 3 months after cyproheptadine withdrawal. Analysis of 3 previously reported cases and this observation shows that cyproheptadine-induced hepatitis is uncommon. Hepatitis occurs within the first month of treatment and is of the cytolytic or mixed-pattern type. Jaundice is constant. Most often, recovery occurs quickly after the discontinuation of cyproheptadine. However, acute hepatitis can be followed by prolonged anicteric cholestasis.     

Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder, characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The attacks can start at any age, but the first attack is usually seen before the second decade of life. We report the case of a young adult male patient with BRIC who presented with recurrent cholestatic jaundice and pruritus with negative work up for all possible etiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with rifampicin and has not suffered another attack on follow up. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.     

Liver disease in children with PiZZ alpha 1-antitrypsin deficiency

We present our experience with 18 pediatric patients with alpha 1-antitrypsin deficiency of the PiZZ phenotype. Fifteen patients (83%) presented with neonatal cholestatic jaundice at a mean age of 2 +/- 0.6 months (+/- S.D.). The male:female ratio was 15:3, indicating a male predominance. All metabolic, infectious and obstructive causes of jaundice were ruled out by appropriate tests in the patients with neonatal cholestasis. Liver biopsy in 14 patients with neonatal cholestasis showed a histological picture of cholestasis in all biopsies; neonatal giant cell hepatitis appeared in seven, increased fibrosis in appeared five and established liver cirrhosis appeared in two biopsies. Patients were followed for a mean of 3.7 +/- 2.4 years (+/- S.D.). Of the 15 patients with neonatal cholestasis, 3 under went liver transplantation because of decompensated liver cirrhosis at 3, 3 1/2 and 7 years. Two patients died at 4 months and 3 years from complications of liver cirrhosis. Of the remaining 10 patients, 3 had histological evidence of liver cirrhosis, and the remaining 7 patients continue to have enlarged liver and spleen with abnormal liver function tests. Of the three patients without history of neonatal cholestasis, only one had enlarged liver and spleen, and the remaining two are healthy with normal liver function tests. Our experience indicates serious liver disease is highly likely to develop in patients with PiZZ alpha 1-antitrypsin deficiency who present with neonatal cholestatic jaundice. Our experience differs from more recent reports on such patients.