Benign recurrent intrahepatic cholestasis. A report of 26 cases

Benign recurrent intrahepatic cholestasis is characterized by attacks of cholestasis. The purpose of our study of 26 patients was to emphasize some features uncommonly or never reported in this disease: (a) in each patient, the attacks of cholestasis were stereotypic; (b) attacks of cholestasis were not associated with pruritus in 15% of our patients; (c) the occurrence of attacks of cholestasis during pregnancy or oral contraceptive use might be a fortuitous coincidence; (d) gallstones were found in several patients with benign recurrent intrahepatic cholestasis and might be present earlier than in the general population; (e) in some of our patients, during attacks of cholestasis, serum transaminases were very high, exceeding 15 times the upper limit of normal; (f) mild portal inflammatory infiltration was found in one third of our patients; (g) no treatment shortened the duration of cholestasis, and in a few patients, plasmapheresis seemed to diminish jaundice and improve biochemical disorders.     

Oral contraceptive induced thrombi of the right heart of a heterozygous protein C-deficient woman--a case report

We reported a 42-year-old heterozygous protein C-deficient woman whose oral contraceptive drug induced thrombi in the right heart and pulmonary artery are resected successfully. In this article, we tried to determine the triggering effect of oral contraceptive usage on thrombus formation in a patient with heterozygous protein C deficiency. Cessation of the oral contraceptive therapy without any additional anticoagulant drug prevented the recurrence of the thrombus formation.     

Hepatobiliary complications of oral contraceptives

Complications secondary to the use of oral contraceptive agents are rare. Hepatobiliary complications, while often dramatic in presentation, occur infrequently. In a patient without predisposing conditions to complications, the benefits achieved with estrogen/progesterone products outweigh the risks. Those conditions that would absolutely and relatively contraindicate the use of oral contraceptives are listed in Table 4. Patients with a past history of liver disease in whom liver function tests have returned to normal may tolerate the introduction of oral contraceptives. They need to be monitored closely for adverse reactions. Patients who have experienced cholestatic jaundice of pregnancy should avoid all contraceptives because of a high risk of disease recurrence. Women whose first-degree relatives have experienced cholestasis of pregnancy or oral contraceptive-induced cholestasis may be at increased risk and should be closely monitored while taking birth-control pills. Women with current or previous benign or malignant hepatic tumors should not take oral contraceptives. Active hepatitis is an absolute contraindication to using birth control pills, although patients with a past history of hepatitis and no evidence of active disease can have a trial of these drugs with close follow-up. A final group of women who should avoid oral contraceptives is those with familial defects of biliary excretion, including the Dubin-Johnson syndrome, Rotor's syndrome, and benign intrahepatic recurrent cholestasis. Dubin-Johnson syndrome is often asymptomatic and may manifest only during pregnancy or during the use of oral contraceptives. The reduction in hepatic excretory function induced by the sex steroids can transform the mild hyperbilirubinemia into frank jaundice. Oral contraceptive agents are the most widely used reversible means of birth control currently available. Fortunately, the complications associated with these drugs are infrequent and may be decreasing due to lower-dose products. Complications still occur, however, and need to be recognized by the general internist as medication-induced problems so the offending drugs can be discontinued and appropriate treatment and follow-up initiated. In addition, patients at risk for the development of complications need to be recognized and advised prior to the introduction of oral contraceptives.     

Plasma exchange treats severe intrahepatic cholestasis caused by dacomitinib: A case report

Rationale:Dacomitinib-induced liver injury is often manifested by mild elevations of transaminases and bilirubin, and severe intrahepatic cholestasis caused by dacomitinib for simultaneous taking orally cytochrome P450 2D6 (CYP2D6) competitive substrates has been rarely reported.Patient concerns:The patient was a 69-year-old woman with non–small cell lung cancer (NSCLC) who was prescribed oral dacomitinib for a month; she was given oral loratadine due to “allergic rhinitis” and metoprolol extended action tablets due to “tachycardia” separately for a few days during the course of dacomitinib treatment. The patient developed liver damage, increased fatigue, yellow urine, and pruritus, with significantly elevated serum levels of bilirubin and glutamyltranspetidase.Diagnosis:Intrahepatic cholestasis, drug-induced liver injury, and NSCLC.Interventions:After admission, the patient was prescribed adenosylmethionine, acetylcysteine, ursodeoxycholic acid capsule, methylprednisolone and fenofibrate for a month, with progressive elevation of liver biochemical parameters. Through drug enzyme gene assays in the liver tissue after percutaneous liver biopsy, we found both CYP2D6*10/*10 and ATP-binding cassette subfamily B member 1 GG variants (rs1045642) positive. After the poor response to the conventional medication, the patient underwent plasma exchange.Outcomes:The patient was discharged after her liver parameters improved; the parameters remained normal at several follow-up visits, and she renewed the NSCLC regimens without dacomitinib after being evaluated by oncologists.Lessons:Dacomitinib can induce severe intrahepatic cholestasis. It is considered that patients with intermediate metabolic CYP2D6 are susceptible to drug-induced liver injury caused by dacomitinib; plasma exchange may be an effective treatment.     

Correlation between cholestasis and infection

This is an overview of cytokine-induced cholestasis, justified by the insufficient knowledge of this frequent type of cholestasis. In the presence of an infectious agent a systemic and intrahepatic production of proinflammatory cytokines results (TNF-alpha, IL-1beta, IL-6 etc.), stimulated by microbial lipopolysaccharides. In patients having systemic infections, the liver has several major functions: source of the inflammatory cytokines produced as a response to infection and a target of these inflammation mediators. The inflammatory cytokines interfere with the activity of both the sinusoidal and canalicular transporting systems. One of the potential consequences of this process is the appearance of cholestasis. An infection can lead to cholestasis despite the absence of direct invasion of the liver by the infectious agent. Particularly the cholestasis produced when the infection generating agent is not located in the liver (sepsis or extrahepatic infections) has been emphasized. The clinical aspect of the diseases associated with this type of cholestasis and the effects of anti-infectious therapy on cholestasis are presented. Cytokine-induced cholestasis represents a common pathogenic path for several diseases: hepatitides that present with an intrahepatic cholestatic pattern (viral, ethanol-induced, NSAID-induced), but also many other infections, which are sometimes overlooked because of the lack of clinical signs. When a preexistent liver disease is present, the cholestasis incidence is higher. In this latter condition, ignorance of this possible mechanism of cholestasis will lead to misdiagnosis and unnecessary tests, sometimes expensive and useless.     

Gallstone dissolution therapy with ursodiol

Ursodeoxycholic acid (ursodiol) has been shown to be an effective oral agent for dissolution of gallstones that also has a favorable safety profile. In the selection of patients as candidates for this treatment, stone characteristics and the functional status of the gallbladder are the two most important criteria. Small, primarily cholesterol stones (radiolucent on plain film) are the most suitable for oral dissolution therapy. In addition, a functioning gallbladder (as evidenced by visualization on oral cholecystogram) is required to concentrate the ursodiol-enriched bile and effect stone dissolution. Ursodiol should not be used during pregnancy, in women likely to become pregnant, or in severe acute or chronic intrahepatic cholestasis. Acute cholestasis and common bile duct obstruction also preclude this treatment. Screening tests include basic laboratory tests of liver function, sonographic evaluation of the gallbladder and biliary tree, plain film of the abdomen, and oral cholecystogram. Since few patients meet all the selection criteria ideally, the decision to undertake treatment with ursodiol must be based on the entire clinical profile and on the patient's willingness to accept the predicted likelihood of success.     

Recurrent intrahepatic cholestasis of pregnancy and chain-like choledocholithiasis in a female patient with stop codon in the ABDC4-gene of the hepatobiliary phospholipid transporter

We report the case of a 40-years-old female patient with recurrent cholestatic liver disease who presented twice with severe intrahepatic cholestasis of pregnancy and pronounced choledocholithiasis between pregnancies. Bile duct stones were removed endoscopically and a laparoscopic cholecystectomy was performed after the second pregnancy. Liver histology revealed intrahepatic cholestasis with portal inflammation and fibrosis, resembling progressive familial intrahepatic cholestasis (PFIC). Molecular genetic studies identified the heterozygous mutation c.957C > T in the ABCB4 gene encoding the hepatobiliary phospholipid transporter. This is the first report of this mutation that introduces a stop codon in an index patient with intrahepatic cholestasis of pregnancy and multiple bile duct stones. In addition, we detected the ABCB11 polymorphism V 444A, which is associated with a decreased expression of the bile salt export pump. Whereas homozygous carriers of the ABCB4 mutation develop PFIC type 3, the heterozygous ABC transporter mutations represent genetic risk factors for cholelithiasis and recurrent cholestatic hepatitis upon challenge with oral contraceptives or during pregnancy. Of note, the patient presented with normal serum gamma-glutamyltranspeptidase activities during pregnancy-associated cholestatic episodes but normal liver enzymes after delivery, whereas choledocholithiasis was associated with high gamma-glutamyl transpeptidase levels. It is unknown whether ursodeoxycholic acid prevents cholestasis or gallstones in patients with ABCB4 deficiency.     

Rapid disappearance of hepatic adenoma after contraceptive withdrawal

We present the case of a 25-year-old woman who developed a large central liver adenoma after 8 years of continuous oral contraceptive use. The first diagnosis was made by ultrasonography, after a rise in plasmatic gamma-glutamyl-transpeptidase and alkaline phosphatase levels was noted. Withdrawal of the oral contraceptive was followed by shrinkage of the adenoma, with complete disappearance 9 months after the diagnosis. Hepatic adenoma (HA) still presents problems in terms of differential diagnosis and clinical management. There are reports of complete or partial regression of an HA after discontinuation of oral contraceptives, but they are poorly documented. To our knowledge, a patient with such rapid disappearance of a large HA has never been reported.     

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.     

Complete spontaneous regression of giant focal nodular hyperplasia of the liver: Magnetic resonance imaging evaluation with hepatobiliary contrast media

Focal nodular hyperplasia(FNH) of the liver is a benign lesion occurring in 0.6%-3% of the general population that probably reflects a local hyperplastic response of hepatocytes to a vascular abnormality. Most lesions are diagnosed incidentally and the natural history of the disease remains largely unknown. It has been shown that most FNH remain stable, or even regress, over a long follow-up period. We present a patient with FNH of the liver who was followed up for 7 years. A 26-yearold woman with a 5-year history of oral contraceptive use was referred to our hospital in February 2005 for further examination of a liver tumour. The diagnosis of FNH was made using magnetic resonance(MR) imaging with hepatospecific contrast media; this technique allows a correct diagnosis, in particular distinguishing FNH from hepatic adenoma, avoiding an invasive procedure such as the lesion biopsy. After 7-year from the diagnosis, we observed the complete spontaneous regression of the lesion by enhanced MR scanning. In this patient, discontinuation of oral contraceptive use and two childbirths may have influenced the natural history of FNH. To our knowledge, in the English literature there is no report illustrating a complete regression of giant FNH but only studies of decreasing in size. The present case suggests that a young patient with giant FNH should be managed conservatively rather than by resection, because FNH has the potential for spontaneous regression.     

Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2)

BACKGROUND: We report two cases of antidepressant induced cholestasis. Case reports: We describe the first reported case of acute cholestasis due to citalopram (selective serotonin reuptake inhibitor) occurring in a patient who also experienced obstetric cholestasis in association with each of three pregnancies; in a second patient cholestasis developed due to dothiepin (tricyclic antidepressant), and six years later due to paroxetine. In both cases liver biopsies showed features of a "pure" cholestasis with total resolution within 1-6 months after withdrawal of the causative drug. Immunostaining for the canalicular transporter, multidrug resistant protein 2 (MRP2), responsible for biliary secretion of several organic anions including bilirubin glucuronides, showed sustained expression in both biopsies as well as relocalisation with appearance of strong staining of the basolateral membrane of the hepatocyte. This finding has also not been reported previously. CONCLUSIONS: We postulate that intracellular redistribution of MRP2 may reflect an adaptive compensatory mechanism which helps in the elimination of the drug or its cholestatic metabolites from the hepatocyte back to the sinusoidal space and subsequent excretion in urine. Changes seen in these two patients differ from findings previously reported in rats where downregulation of mrp2 occurs in response to experimentally induced cholestasis. We speculate that the rat is more advanced than humans in its ability to downregulate canalicular transporter expression as protection against progressive intrahepatic cholestasis.     

Renal artery thrombosis in a young woman taking oral contraceptives.

Retrospective studies indicate that oral contraceptive use is associated with an increased risk of venous thromboembolic disease, but the evidence linking oral contraceptive use with the development of arterial thrombosis is limited. In view of this paucity of evidence, the case report of a young women taking oral contraceptives and treated at the Naval Regional Medical Center in San Diego for sudden renal artery thrombosis without any predisposing cause, is of some significance. The 22 year old patient had no physical evidence or history indicative of trauma or systemic disease; however, she reported taking Orthonovum 1/50 for the 6 months preceeding the event and smoking a pack of cigarettes/day. These factors, in combination, may have predisposed her to arterial thrombosis. Included is a photograph of the patient's angiograph showing the occlusion.     

A case of carbimazole-induced intrahepatic cholestasis. An immune-mediated reaction?

A patient is described with cholestatic hepatitis following the use of carbimazole. A liver biopsy specimen showed intracanalicular cholestasis and some mononuclear cell infiltrate in the portal triades, consistent with drug toxicity; indications of an autoimmune or viral pathogenesis were absent. Rechallenge with the drug precipitated jaundice and disturbed liver function once more. Carbimazole induced a blastogenic response of patient lymphocytes in vitro. Both may suggest the involvement of an immune-mediated reaction, especially as it has been shown that sensitized lymphocytes may produce a cholestatic factor on stimulation with antigen.     

Cholestatic hepatitis induced by the amoxicillin-clavulanic acid combination. A case and review of the literature

We report the case of a patient who developed jaundice after receiving amoxicillin-clavulanic acid for 7 days. Laboratory features were consistent with acute cholestatic hepatitis. Histopathological examination of a liver specimen showed cholestasis. Complete recovery occurred within 2 months after withdrawal of the drug. Analysis of the 24 reported cases of amoxicillin-clavulanic acid induced hepatitis revealed a predominantly cholestatic syndrome occurring soon after drug administration. In all cases, hepatic dysfunction disappeared within 1 to 3 months after discontinuation of the drug. Because of the small number of cases in contrast with the widespread use of this drug, associated with blood hypereosinophilia or eosinophilic infiltration of portal triads in some cases, a hypersensitivity phenomenon is suggested.     

Bile salt export pump deficiency disease: two novel,late onset,ABCB11 mutations identified by next generation sequencing

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATP-dependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel mis-sense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.     

Unusual Course of Congenital Hypothyroidism and Route of the L-Thyroxine Treatment in a Preterm Newborn

Congenital hypothyroidism (CH) is the most common endocrine pathology in neonates. Inappropriate treatment of CH is complicated by irreversible brain damage or low IQ score. Hormone replacement therapy with L-thyroxine (L-T4) is sufficient for a very large proportion of patients. However, during treatment, the patient needs to be carefully monitored for presence of factors which might affect the absorption or bio-availability of the drug as well as its dose. Herein, we report a preterm newborn with CH who presented with gastrointestinal problems mimicking necrotizing enterocolitis. The clinical course was also complicated by cholestasis. The L-T4 replacement treatment was switched from oral route to parenteral. After resolution of the cholestasis, L-T4 treatment was continued successfully by the oral route.     

甲状腺功能亢进症伴严重药物性胆汁郁积性肝炎1例并文献复习

甲状腺功能亢进症（甲亢）本身可导致肝功能损害,而抗甲状腺药物亦可引起肝功能损伤.但出现严重药物性胆汁郁积性肝炎的病例比较少见,临床治疗较为困难.本院收治1例,在治疗甲亢的基础上,采用甲强龙静脉脉冲冲击联合口服强的松的方案,降低患者胆红素水平,使肝功能恢复正常,甲亢亦得以控制.     

Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

Progressive familial intrahepatic cholestasis type 3 （PFIC3） is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System （MARS） has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.     

Malignant hypertension associated with use of oral contraceptives.

A 26-year-old woman who had been taking an oral contraceptive preparation for two years developed malignant hypertension. Investigation failed to elicit any renal or other cause for her hypertension, but control of blood pressure was obtained by withdrawal of the oral contraceptive agent and antihypertensive therapy. Subsequently, after withdrawal of therapy, the blood pressure remained near normal. The patient had a previous history of hypertension during pregnancy; she was also overweight.