Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.

BACKGROUND/AIMS: Hepatotoxicity has been previously suspected by national regulatory agencies in 26 patients in causal relationship with the treatment by kava extracts commonly used as herbal anxiolytic drugs. METHODS: A quantitative causality assessment was undertaken using the system of the Council for International Organizations of Medical Sciences, scale of objective probability scoring. RESULTS: Causality was unassessable, unrelated, or excluded in 16 patients owing to lack of temporal association and causes independent of kava or comedicated drugs. Low Council for International Organizations of Medical Sciences scores additionally resulted in excluded or unlikely causality assessments (n=2), leaving a total of eight patients with various degrees of causality for kava +/- comedicated drugs. Only one out of these eight patients adhered to the regulatory recommendations regarding both daily dose (<or=120 mg kavapyrones) and duration of therapy (<or=3 months) and experienced toxic liver injury with a probable causality for kava. In six cases with kava overdose and/or increased duration of kava treatment causality for kava was possible (n=3) and for kava together with the comedicated drug(s) possible (n=2) or probable (n=1). CONCLUSION: Kava taken as recommended is associated with rare hepatotoxicity, whereas overdose, prolonged treatment, and comedication may carry an increased risk.

Toxic liver diseases caused by drugs, herbs and dietary supplements are often recognized late because their hepatotoxic potency is considered to be minimal or non-existent and specific laboratory parameters to definitively establish the diagnosis are lacking. As gold standard for the diagnosis, a positive (unintentional) re-exposure test is considered which is seldom available. A system for evaluation is therefore necessary which takes into account various parameters and defines the grades of causality. By means of a qualitative pre-test with a few questions a screening may be possible as to whether the causality is not probable or not evaluable. Subsequently, a quantitative assessment of the degree of the causality with a main test should be done; this corresponds to the slightly modified and well validated score of the CIOMS (Council for International Organizations of Medical Sciences). The evaluation is achieved using various criteria such as latency period, time between the end of the therapy and begin of the reaction, course of values for the enzyme activities of the liver after cessation of the therapy, risk factors such as age, alcohol consumption and comedication, exclusion of diseases of other organs including chronic liver disease, previous information about hepatotoxicity of the alleged substance and possible results of an unwanted re-exposure. The various answers to these questions are quantitatively assessed, the resulting scores added, and finally an assignment to one of the grades of causality is made. If, on the basis of the main test, there are still doubts about the correct diagnosis, a further test is required to consider the differential diagnosis of additional diseases and chronic liver diseases of other causes. This stepwise approach is essential since ad-hoc decisions regarding causality are not without problems, and other diseases as causes for increased liver values are easily overlooked and not treated adequately in time. By means of this procedure an improvement in the drug safety can be expected, which is fruitful for the patient and helpful to the physician in charge, the health institutions and the drug companies.

Vague upper abdominal pain, weight loss (10 kg) and recurrent bouts of fever had been present for several months in a 77-year-old woman. Abdominal ultrasonography in the region of the head of the pancreas and duodenum had demonstrated several lymphomas, some of them with "air streaking". This finding suggested penetration from the duodenum to neighbouring lymph nodes. Plain film of the abdomen did not show free air, but at gastroscopy a covered perforation into the surrounding lymph nodes was found. At first lymphoma or Crohn's disease were considered in the differential diagnosis. But the finding of acid-fast bacteria in a biopsy from the pelvic crest suggested intestinal tuberculosis with dissemination. This diagnosis was confirmed by the direct demonstration of Mycobacterium tuberculosis in gastric juice. Under tuberculostatic treatment with daily 0.3 g isoniazid, 0.45 g rifampicin, 0.8 ethambutol and 1.5 g pyrazinamide, as well as 50 mg prednisolone to prevent stricture, the size of the tuberculous ulcer had markedly decreased within 2 weeks. Follow-up gastroscopy after 6 months showed almost complete healing without stricture. However rare, gastrointestinal tuberculosis should not be forgotten in the differential diagnosis because it can imitate a large variety of gastrointestinal diseases.

Upper abdominal ultrasound imaging in a 63-year-old woman who had been hypertensive for ten years revealed a tumour at the lower pole of the left kidney. It protruded from the renal surface and gave dense echoes, suggestive more of an angiomyolipoma than a hypernephroma. The former diagnosis was reenforced by the angiographic appearance and confirmed by biopsy at the time of surgery. Nephrectomy was performed and the postoperative course was without complication.