Clinical case: 17-04-2012

Carlos Mejía Chew

MIR 2

34 Y/O MALE HIV+ PATIENT WITH HYPOPHOSPHATEMIA

AND GLUCOSURIA

Past medical history • Multiple episodes of gonococci urethritis

• Acuminated condylomas 2003

• Atopic dermatitis

• Sept 2005: HIV (Stage A2: VL 10,000 and CD4+ 390)

• April 2006:

• HAART (VL 8,000 and CD4+ 199) with TDF+FTC+LPV/r • Chronic HBV (VL out of range; AST 50, ALT 82)

• Oct 2006

– HIV: VL <50 and CD4+ 527 – HBV: VL undetectable and normal liver enzymes

Social history

• Difficulty concentrating and lack of attention since early childhood: Mild intellectual disability (1987)

• Single MSM

• Works as a hair dresser

Current History

• During follow-up, in a routine analysis the patient presented hypophosphatemia and glucosuria

• Patient was asymptomatic

• No clinical, immunologic or viral failure was documented

Lab results

Blood chemistry

• Glucose 88 mg/dl

• Na+ 141 mEq/L

• K+ 3,8 mEq/L

• Ca2+ 9,4 mg/dl

• P- 2,24 mg/dl

• Urea 15 mg/dl

• Creatinine 1,02 mg/dl

• CrCl 103 ml/min/1.73m2

Urine

• Glucose 100 mg/dL

• Protein (-)

• WBC < 5

• RBC (-)

• No casts

CBC: within normal range

Clinical Problem

34 y/o male co-infected (HIV-HBV) patient with renal glucosuria and hypophosphatemia, 6 months after initiation of HAART (TDF+FTC+LPV/r)

What test would you do?

Renal glucosuria

“Renal glucosuria can be caused primarily either by mutations in the Na+-glucose transporter in the proximal tubulus or by tubular damage”

Siegenthaler’s Differentila Diagnosis in Internal Medicine. From Symptom to Diagnosis . First English edition, 2007.

Is there a tubular disorder?

Siegenthaler’s Differentila Diagnosis in Internal Medicine. From Symptom to Diagnosis . First English edition, 2007.

What test would you do?

Urinary electrolytes, proteins and amino acids

• Alpha-1-microglobulin: 34mg/24hr

• Beta-2-microglobulin: 3mg/24hr

• Phosphate: 951 mg/24h

• Fraction of phosphate excretion: 32,56%

• Glucosuria

Causes of tubular dysfunction

Inhereted

• Cystinosis

• Wilson disease

• Hereditary tyrosinemia

• Lowe syndrome (oculocerebrorenal osteodystrophy)

Acquired

• Pyelonephritis

• Fanconi-de Toni-Debre syndrome

• Multiple Myeloma

Siegenthaler’s Differentila Diagnosis in Internal Medicine. From Symptom to Diagnosis . First English edition, 2007.

Causes of tubular dysfunction

Inhereted

• Cystinosis

• Wilson disease

• Hereditary tyrosinemia

• Lowe syndrome (oculocerebrorenal osteodystrophy)

Acquired

• Pyelonephritis

• Fanconi-de Toni-Debre syndrome

• Multiple Myeloma

Siegenthaler’s Differentila Diagnosis in Internal Medicine. From Symptom to Diagnosis . First English edition, 2007.

Fanconi syndrome…HIV+ on HAART

• Dysproteinemias (MM, Amyloidosis)

• Heavy metals (cadmium, lead, mercury, platinum, and uranium)

• Pharmacologic: TDF, ADV, valproic acid, aminoglycosides, tetracycline

American Journal of Kidney Diseases, 2011-05-01

TDF induced Fanconi

However…

• NO increase in Cr or decrease in CrCl

• NO aminoaciduria

Social history

• Difficulty concentrating and lack of attention since early childhood: Mild intellectual disability (1987)

• Single MSM

• Works as a hair dresser

Clinical Problem

34 y/o male with mild cognitive impairment, co-infected (HIV-HBV) patient on HAART (TDF+FTC+LPV/r) with renal tubular dysfunction and hyperphenylalanuria

Hyperphenylalanuria? Serum Phe Hyperphenylalanemia

• Phenylketonuria (PKU)

• Tetrahydrobiopterin (BH4) deficiency

• Tyrosinemia

Zelikovic I. Aminoaciduria and glycosuria. In: Barratt TM, Avner ED, Harmon WE, eds. Pediatric Nephrology. 4th ed. Lippincott Williams & Wilkins; 1999:507-27.

Hyperphenylalanuria? Serum Phe Hyperphenylalanemia

• Phenylketonuria (PKU)

• Tetrahydrobiopterin (BH4) deficiency

• Tyrosinemia

Zelikovic I. Aminoaciduria and glycosuria. In: Barratt TM, Avner ED, Harmon WE, eds. Pediatric Nephrology. 4th ed. Lippincott Williams & Wilkins; 1999:507-27.

Other tests

What test would confirm the diagnosis?

Diagnosis

1. TDF induced renal tubular dysfunction

2. Moderate form of PKU

3. Chronic HBV

How should this patient be managed?

1. PKU

2. TDF induced tubular dysfunction

1. PKU: A quick review

Overview

• Most common inborn error of amino acid metabolism

• Autosomal recessive

• Mutations in the PAH gene 12q24.1 (98%)

• > 500 different mutations have been identified

Blau N. Phenylketonuria and BH4 Deficiencies. First edition. UNI-MED Verlag, Bremen 2010.

Where’s the defect?

Blau N. Phenylketonuria and BH4 Deficiencies. First edition. UNI-MED Verlag, Bremen 2010.

Mode of inheritance

Blau N. Phenylketonuria and BH4 Deficiencies. First edition. UNI-MED Verlag, Bremen 2010.

Clinical manifestations • Musty odor

• Intellectual disability (most common)

• Fair skin and hair

• Eczema

• Sclerodermalike plaques

• Epilepsy (50%) and extrapyramidal manifestations

Sanjurjo P, Baldellou A. Diagnóstico y tratamiento de las enfermedades metabólicas hereditarias. T Tercera edición. Editorial Ergon, Madrid 2010.

Diagnosis and Classification

• Screening (TMS / Guthrie test)

• Serum phenylalanine (Phe) > 240 µmol/L

– Mild 240-600 µmol/L

– Moderate 600-1,200 µmol/L

– Classic PKU > 1,200 µmol/L

Sanjurjo P, Baldellou A. Diagnóstico y tratamiento de las enfermedades metabólicas hereditarias. T Tercera edición. Editorial Ergon, Madrid 2010.

Treatment • Muldisciplinary approach

• Low Phe diet

• Dietary supplements (LNAA, Folinic acid)

• Tetrahydrobiopterin (SAPROPTERIN)

– BH4-responsive PKU > 4 y/o

– All patients with BH4 deficiency

1) Blau N. Phenylketonuria and BH4 Deficiencies. First edition. UNI-MED Verlag, Bremen 2010. 2) Sanjurjo P, Baldellou A. Diagnóstico y tratamiento de las enfermedades metabólicas hereditarias. T

Tercera edición. Editorial Ergon, Madrid 2010.

How should this patient be managed?

1. PKU

2. TDF induced tubular dysfunction

2. TDF induced tubular dysfunction

Would you change HAART? HIV/HBV+ patient

Our management

• TDF was stopped

– Tubular dysfunction subsided

• 3TC was initiated and LPV/r maintained

• HBV: VL remains undetectable

– LFT in normal range

– Fibroscan: Kpa 5,4 (F0-F1)