Case Report

Marked Hypophosphatemia with Decreased Serum 1,25-Dihydroxyvitamin

D in a Patient

with Hepatocellular Carcinoma Complicating Liver Cirrhosis Yuzo MlZUNO, Naohiko MASAKI, Hideki HASHIMOTO, Itsuro OGATA, Chikara AlZAWA, Kenji FUJIWARA, Gotaro Toda, Masaya MORI*, Rikuo

MACHINAMI* and Kiyoshi


A 61-year-old male with hepatocellular carcinoma (HCC) complicating liver cirrhosis presented hypophosphatemiaprogressing with HCCexpansion and serum a-fetoprotein elevation. These changes were associated with an increased fractional excretion of phosphate and decreased theoretical phosphate threshold. There was increased nephrogenous cyclic adenosine monophosphate despite normal serum parathyroid hormone. Serum 1,25-dihydroxyvitamin D levels were markedly reduced with normal 25-hydroxyvitamin D levels. There were no symptoms of osteomalacia, however, a slightly increased osteoid seam was elicited on autopsy. The hypophosphatemia could be explained by presumed secretion from HCCof humoral factors which have a phosphaturic effect and also inhibit 25-hydroxyvitamin D-l a -hydroxylase in renal tubular cells. Key words: Phosphaturic





Oncogenic osteomalacia




phosphatemia has received much attention clinically. Humoral factors such as parathyroid hormone (PTH)-related protein or PTH-like peptides, which

resemble but are different from PTH, have been proposed to be released by malignant cells in patients with humoral hypercalcemia of malignancy (HHM) (1). Recently, the amino acid sequences and com-

plementary DNAcoding of PTH-related protein were determined by two independent laboratories (2,

3). Although PTH stimulates mitochondrial 25hydroxyvitamin D-l a -hydroxylase [25(OH) D-l a hydroxylase] in renal tubular cells and increases serum levels of 1,25-dihydroxyvitamin D [1,25(OH)2D], most patients with HHMexhibit a marked reduction in 1,25(OH)2D levels despite a normal range of 25(OH)D (4), and hence the elaboration of renal 25(OH)D-1 a -hydroxylase

From First Department of Received for publication Reprint requests should Faculty of Medicine,

D-l a -hydroxylase,

Humoral hypercalcemia


inhibitors from malignant cells has been hypothesized. Such factors were recently demonstrated in tumor extracts from an experimental model of HHMand were partially characterized (5). A similar factor maybe present in serum of patients with oncogenic osteomalacia

(6, 7). Here, we report a

patient with hepatocellular carcinoma (HCC) complicating liver cirrhosis (LC), in which hypophosphatemia was accompanied by low serum 1 ,25(OH)2D levels, and could be attributed to such factors. CASE REPORT

A 61-year-old Japanese man with HCCcomplicating LC was admitted to Tokyo University Hospital on May 9, 1989, because of somnolence and disorientation. He had a blood transfusion in April 1958 when he underwent cranioplasty for skull

Internal Medicine, *Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo February 2, 1990; Accepted for publication September 18, 1990 be addressed to Naohiko Masaki, MD,First Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan

Jpn J Med Vol 30, No 1 (January,

February 1991)


Mizuno et al

recognized in both liver lobes, he had undergone

finger-breadths below the xiphoid process. Dilated veins, passing upwards, were noted on the surface of the abdomen. No superficial lymph nodes were palpable. Laboratory findings are shown in Tables 1 and 2. Urinalysis was noncontributory. Peripheral blood cell count showed moderate anemia with throm-

tumors and endoscopic sclerotherapy for esophageal varices, four times each. On April 22, 1989, he suffered somnolenceappearing soon after massive

transferase (AST) and total bilirubin were slightly increased with markedly elevated ammoniumlevels. Arterial blood gas analysis showed marked chronic

fracture. He had no habit of alcohol drinking. He was found to have LC, of which the origin was suspected

to be posttransfusional

non-A, non-B

hepatitis viral infection, and esophageal varices in May 1982. Since June 1987 when multiple nodular tumors of up to 7 cm in diameter, were first transcatheter



(TAE) for the

esophageal bleeding (800 ml) and diarrhea that followed

the 4th sclerotherapy

performed 5 days

previously. Disorientation developed 3 days before admission.

On admission, his blood pressure was 120/76

mmHg; pulse

rate 68/min,


and body

temperature 35.7°C. The patient was somnolent with bilateral flapping tremor, corresponding to coma

grade II (Sherlock). Conjunctivas were moderately anemic and slightly



spiders were

noticed on his chest. Examination of the heart, lungs and extremities was unremarkable. The abdomen was slightly distended due to moderate ascites. The irregular, firm and dull-edged liver was palpable five


respiratory Corrected

Serum levels

of aspartate


alkalosis with metabolic acidosis. serum calcium (cCa) was slightly de-

creased with a fractional excretion below 1 %. There was a marked decrease in serum phosphorus (iP),

accompanied by increased fractional excretion of phosphate (FEp) and diminished theoretical phosphate threshold (TmP/GFR). Serum PTH levels were within the normal range, whereas nephrogenous cyclic adenosine monophosphate

(NcAMP)levels were markedly increased. 25(OH)D


were within


the normal range,

though serum 1 ,25(OH)2D levels were remarkably decreased.

Bone X-ray examination



Looser's zone. Table 3 shows the changes of serum

Table 1. Laboratory data on admission2*. U rine PH p ro te in su g a r sedi m en t H em a to lo g ic a l W h ite b lo o d ce ll (/ ォ 1) R ed b lo o d c e ll ( x ¥0 3/ a 1) H b (g / d l) H e m ato crit (% ) P lat ele t ( x lO4/ ォ l) P ro th r o m b in tim e (s) (% ) F ib rin o g en (m g / d l) B io c h e m ica l T o ta l p ro tein (g / d l) A lb u m in (g / d l) C h o lin e ste ra se (U / l) AST (Karmen unit) ALT (Karm en unit) LDH (U /l)

5. 5 (- ) (- ) n .p . 6 ,2 0 0 242 8. 1 23. 7 9.0 12 . 1 75 13 0 8.4 3. 4 73 10 1 27 2 12

A L P (K in g -A rm stro n g u n it) r -G T P (IU / l) T o ta l b iliru b in (m g / d l) D ire ct b iliru b in (m g /d l) T o ta l c h o leste ro l (m g/ d l) T rig ly c erid e (m g /d l) Ammonium ( a g/dl) BU N (mg /dl) C rea tin in e b (m g/ d l) Sodium (mEq/1) P o t a ss i u m ( mE q / 1 ) C h lo rid e (m E q / 1) Magnesium (mg/dl) IC G R 15 (% ) a -F e to pr ot ei n ( ng /m l ) S e ro lo g ic a l C RP ST S H B sA g H B sA b H B cA b

10. 9 92 2. 2 1. 1 168 97 2 54 25 1. 5 128 4 .8 10 3 3.4 22 16 3 (ア ((((-

) ) ) ) )

aALP, alkaline phosphatase; STS, serological test for syphilis bEndogenous creatinine clearance (24 h) = 40 ml/min 82

Jpn J Med Vol 30, No 1 (January,

February 1991)

Hypophosphatemia in Hepatoma Table



data on admission


E nd ocrin olo gical (n orm al range) PTH- M ( pg/ mi) 46 5 (1 80- 560 ) PTH intactO (pg/ml) 42 (23-73) 2 5(O H )D (ng/m l) 26 (10- 30) l,25(OH)2D (pg/mi) < 8 (20-50) N ep hrogen ou s CA M P (amol/dlGF) 15 ,9 (0.8^2.8)

A tr erial bloo d gas p H 7 .40, pC O2 17. 9 m mHg , p O2 102m mHg H C O r H . O mm o l / l Ca, P metabolism13 Seru m corrected Ca (mg/dl) 8.1 -8.4 S eru m iP (m g/d l) 0.5- 1.1 Urinary Ca excretio n (mg/day) 1 0-20 U ri nary iP excretio n (m g/d ay) 90 - 230 Fractional excretion of Ca (%) 0.43-0.96 Fractional excretion of P (%) 35-40 T m P /G FR (m g/d l) 0 .34- 0 .69

a iP, inorganic phosphorus; TmP/GFR, theoretical phosphate threshold; PTH, immunoreactive parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1 ,25-dihydroxyvitamin D; CAMP, cyclic adenosine monophosphate

b Values denote ranges of 3 separate determinations during hospitalization c Value was determined by immunoradiometric assay (Allegro) Table 3. Changes of serum cCa, serum iP, FEp and TmP/GFR in relation serum a-fetoprotein levels and tumor size.


P a ra m e tersa

Norm al Da te ra n g e l l/ 2 5 / 1 98 7 9 / 2 2 / 1 9 8 8 3/ 8/ 1 98 9 5 / 1 5 / 1 9 8 9

c c a (m g / d l)

8 .5 - 10 .5

9 .1

8 .6

8 .7

8 .1

iP (m g / d l)

2 .5 - 4 .5

4 .1

2 .4

1 .2

0 .5

< 20

10 .6

2 2 .8

3 4 .4

3 5 .0

4 .0

1 .9

0 .8

0 .4

Marked hypophosphatemia with decreased serum 1,25-dihydroxyvitamin D in a patient with hepatocellular carcinoma complicating liver cirrhosis.

A 61-year-old male with hepatocellular carcinoma (HCC) complicating liver cirrhosis presented hypophosphatemia progressing with HCC expansion and seru...
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