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We read the review article with great interest and it really guided us
managing a very complex case we encountered in our hospital recently. The
patient had acute liver failure secondary to simvastatin on admission and
patient recovered fully only with supportive care. The details of the case
are as follows:
71-year-old African American male presented to the ER with
generalized weakness, mus...
71-year-old African American male presented to the ER with
generalized weakness, muscle pains and shortness of breath on exertion of
3 days duration. Patient had difficulty rising from sitting position and
could not lift his arm above the shoulder.
Patient’s past history included cardiomyopathy with very low left
ventricle ejection fraction (15%), dyslipedemia and CAD. Patient smoked a
packet of cigarettes per day for 30 years and used to drink alcohol every
day until 2 years ago when he stopped both. His medications included
Furosemide 40 mg daily, Famotidine 20mg daily, Zolpidem 5mg daily,
Digoxin 0.125 mg daily, Carvedilol 6.25 mg PO BID, ASA 325 mg daily,
Simvastatin 20 mg and Fosinopril 20 mg po daily.
On physical examination patient was awake alert and fully oriented.
Systemic examination was unremarkable except for decreased muscle power in
proximal muscles of both upper and lower extremities and hepatomegaly.
Lab studies on admission showed BUN 82 mg/dl, Creat 1.7mg/dl, WBC
8780/microL, HGB 11.5 gm/dl and Platelet count was 107000/microL. AST was
1198 IU/L and CPK was 253 IU/L (MB index 1.5). PT was 20 sec, PTT 30.3 sec
and INR was 3. Troponin I was 2.4 ng/ml.
Patient’s clinical condition worsened in next two days and patient
developed hepatic encephalopathy and worsening renal function. Along with
drowsiness and flapping tremor, lab studies showed rising AST, ALT, total
and direct bilirubin and PT. BUN was rising and platelet count was
dropping. Peripheral smear showed high reticulocyte count along with
anemia, burr cells and schistocytes.
Patient was on Sodium Bicarbonate
drip and intravenous saline. Patient’s serum uric acid was found to be
above 20-mg/dl. After day four clinical condition changed for the better
and his AST, ALT started to come down along with bilirubin levels. Lab
values are presented in table 1. below. Patient’s Prothrmobin time and
Platelet counts were also recovering by day 5 of hospital stay and they
almost returned to baseline by day 6 and 7.
Liver imaging in the form of
Ultrasound and MRI of abdomen only showed mild ascites and hepatomegaly.
Serum Aldolase was elevated and Hepatitis profile was negative. Patient
made a dramatic recovery by day 7 and was ready for discharge from the
hospital. Patient probably was a candidate for liver transplant on day 3 of hospital
stay but a dramatic recovery followed that day when we were discussing the
options with the family.
1. Bhatia V. Massive Rhabdomyolysis with Simvastatin precipitated by
Amoxicillin . J Postgrad Med 2004;50:234-235.
2. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty
Hepatology. 2005 Apr;41(4):690-5.
3. Anfossi G, Massucco P, Bonomo K, Trovati M Prescription of statins to
dyslipidemic patients affected by liver diseases: a subtle balance between
risks and benefits. Nutr Metab Cardiovasc Dis. 2004 Aug;14(4):215-24. Review.
Might both the hyperdynamic circulation and encephalopathy in acute
liver failure be the products of decompensated anaerobic glycolysis? That
is to say might the most morbid metabolic defect be an inability to
recycle lactate and the other by-products of anaerobic glycolysis such as
glutamine? If so might outcome from acute liver failure be averted by
addressing the problem?
Anaerobic glycolysis appears to be the preferred means of
replenishing ATP stores in healing wounds and regenerating organs and is
accompanied by a marked increase in tissue lactate. In these
circumstances the lactate may become the preferred substrate for ATP
resynthesis by oxidative phosporylation by adequately oxygnated organs,
such as the heart and liver, as occurs in exercise. In liminating the need
for ATP utilisation to generate substrate for the Krebs cycle the
efficincy, and hence net ATP yield, is increased by these means. It
requires some 20 times more glucose to generate one mole ATP by anaerobic
glycolysis than by oxidative phosphorylation. This is achieved by
increasing the rate of tissue perfusion and the efficiency of glucose
utilisaation largely as a rsult of an accompanying increase in regional
temperature. Dependncy upon anaerobic glycolysis for ATP rsynthesis is not
complete for oxygen consmption, and by inference ATP yield from oxidative
phosphorylation, rises as the temperature and metabolic rate increase
In isolated perfused rat livers hepatic oxygen consumption was
transport dependent only when perfusate conditions contained glucagon,
epinephrine, or dexamethasone or a high lactate concentration . In the
absence of a metabolic load, (substrate and hormone-free perfusate),
hepatic oxygen consumption was transport independent even at a hepatic
venous oxygen saturation as low as 10%. As tissue blood flow is said to
be demand dependent these data raise the possibility that it is the demand
for nutrient substrate rather than for oxygen that is the prmary
determinant of determines of the rate of tissue blood flow. In other words
the rates of oxygen consumption andoxidative phosphorylation might be
largely dependent upon the regional temperature and accompanying metabolic
rate. If so tissue lactate concentration might be the most important
determinant of tissue blood flow in isothermic conditions.
If the rate of ATP hydrolysis determines the magnitude of demand for
nutrient substrate delivery to the liver at any moment the rate of blood
flow needed to meet demand should be reduced if ATP resyntheis were
shifted from anaerobic glycolysis to oxidative phosphorylation. Anaerobic
threshold should also be increased . The major benefit expected from
these changes would be enabling tissue nutrient requirements to be met
without imposing an incrasing and potentially overwhelming workload on the
Although artificial liver support devices remain unproven in efficacy
in acute liver failure  some believe that plasmapheresis may be of
benefit . In designing an artificial liver support device attention has
focused on correcting the abnormalities in blood. This approach overlooks
a primary causes of death. Cerebral oedema and death may be caused by a
rise in intracrananial pressure in long before cardiac arrest can
occur . Cardiac arrest is the usual cause of death in patients who have
developed sepsis and multiple organ dysfunctions. The cause of cardiac
arrest in these patients might well be an overwhelming workload on the
heart imposed by a need to meet an insatiable need for nutrient deliery to
support ATP resynthesis by anaerobic glycolysis.
Removing the cause is clearly of paramount importance in treatimg a
patient with acute liver failure and/or multiple organ dysfnction. In
acute liver failure that is often accomplished for the simple reason that
the patient is no longer exposed to the precipitating factor, commonly
paracetamol. How might the myocardial workload be reduced to prvent a
cardiac arrest recognizing that any antecdnt cardiac failure can be
expected to make the intracranial pathology worse by both direct and
One way might be clamping the tissue pH at an abnormally low level
whilst maintaining the adequacy of tissue perfusion . This can be
expected to pregulate oxidative phosphorylation and in so doing decrease
the demand for nutrient delivery needed ATP resynthesis by anaerobic
glycoloysis. A theoretical risk is that this might compromise the recovery
of the liver. If the intrahepatic pH could be maintained at normal or
even high levels whilst the pH in all other tissues was lowered that risk
might be eliminated. The same objective might be achieved by increasing
effective nutrient density with an infusion of insulin, potassium and
glucose or inducing a lipid shift by increasing the levels of fatty acids
in blood. This approach might even be the most effective means of
addressing the intracranial pathology .
A different approach, possibly most suited to patients who had
developed pulmonary dysfunction, might be to improve hepatic oxygenation
with by intraperitonal and/or enteric oxygenation (8,9). A unintended
consequence might, however, be an increase in free radical generation and
associated tissue injury.
1. Dahn MS, Lange MP, Benn S. The influence of hepatic venous oxygen
saturation on the liver's synthetic response to metabolic stress.
Proc Soc Exp Biol Med. 1999 May;221(1):39-45.
2. Successful evolutionary adaptation to environmental stress?
Richard G Fiddian-Green Heart Online, 14 Jul 2004 eLetter re: D A Lawlor,
G Davey Smith, R Mitchell, and S Ebrahim Temperature at birth, coronary
heart disease, and insulin resistance: cross sectional analyses of the
British women’s heart and health study Heart 2004; 90: 381-388
3. J G O’Grady
Acute liver failure
Postgrad Med J 2005; 81: 148-154
4. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. Role of
plasmapheresis in the management of acute hepatic failure in children.
Ann Surg. 2001 Sep;234(3):418-24.
5. Punch JD. Bridges to transplantation.
Anesthesiol Clin North America. 2004 Dec;22(4):863-9.
6. Fiddian-Green RG Gastric intramucosal pH, tissue oxygenation and
Br J Anaesth. 1995 May;74(5):591-606.
7. Might intracranial pressure be a passive reflection of
Richard G Fiddian-Green (16 November 2004) eLetter re: M Czosnyka and J
Monitoring and interpretation of intracranial pressure
J Neurol Neurosurg Psychiatry 2004; 75: 813-821
8. Haglund U. Therapeutic potential of intraluminal oxygenation.
Crit Care Med. 1993 Feb;21(2 Suppl):S69-71.
9. Gross BD, Sacristan E, Peura RA, Shahnarian A, Devereaux D, Wang
HL, Fiddian-Green R. Supplemental systemic oxygen support using an
intestinal intraluminal membrane oxygenator.
Artif Organs. 2000 Nov;24(11):864-9.